A Narrative Review: Repurposing Metformin as a Potential Therapeutic Agent for Oral Cancer.

Oral cancer, particularly oral squamous cell carcinoma (OSCC), is a significant global health challenge because of its high incidence and limited treatment options. Major risk factors, including tobacco use, alcohol consumption, and specific microbiota, contribute to the disease's prevalence. Recently, a compelling association between diabetes mellitus (DM) and oral cancer has been identified, with metformin, a widely used antidiabetic drug, emerging as a potential therapeutic agent across various cancers, including OSCC. This review explores both preclinical and clinical studies to understand the mechanisms by which metformin may exert its anticancer effects, such as inhibiting cancer cell proliferation, inducing apoptosis, and enhancing the efficacy of existing treatments. Preclinical studies demonstrate that metformin modulates crucial metabolic pathways, reduces inflammation, and impacts cellular proliferation, thereby potentially lowering cancer risk and improving patient outcomes. Additionally, metformin's ability to reverse epithelial-to-mesenchymal transition (EMT), regulate the LIN28/let-7 axis, and its therapeutic role in head and neck squamous cell carcinoma (HNSCC) are examined through experimental models. In clinical contexts, metformin shows promise in enhancing therapeutic outcomes and reducing recurrence rates, although challenges such as drug interactions, complex dosing regimens, and risks such as vitamin B12 deficiency remain. Future research should focus on optimizing metformin's application, investigating its synergistic effects with other therapies, and conducting rigorous clinical trials to validate its efficacy in OSCC treatment. This dual exploration underscores metformin's potential to play a transformative role in both diabetes management and cancer care, potentially revolutionizing oral cancer treatment strategies.

The Impact of PAD4-dependent Neutrophil Extracellular Trap Formation on the Early Development of Intestinal Fibrosis in Crohn's Disease.

BACKGROUND AND AIMS: During early phases of inflammation, activated neutrophils extrude neutrophil extracellular traps (NETs) in a PAD4-dependent manner, aggravating tissue injury and remodelling. In this study, we investigated the potential pro-fibrotic properties and signalling of NETs in Crohn's disease (CD). METHODS: NETs and activated fibroblasts were labelled on resected ileum from CD patients by multiplex immunofluorescence staining. NETs-treated human primary intestinal fibroblasts were analysed by bulk RNA-sequencing to uncover cell signalling pathways, and by high-throughput imaging to assess collagen production and migratory activity. Consequentially, TLR2/NF-kB pathway was evaluated by transfection of CCD-18Co fibroblasts with NF-kB-luciferase reporter plasmid, incorporating C29 to block TLR2 signalling. A chronic DSS mouse model was used to define the specific role of PAD4 deletion in neutrophils (MRP8-Cre, Pad4fl/fl). RESULTS: Immunofluorescence showed spatial co-localisation of NETs and activated fibroblasts in ileal ulcerations of CD patients. Transcriptomic analysis revealed upregulation of pro-fibrotic genes and activation of TLR-signalling pathways in NETs-treated fibroblasts. NETs treatment induced fibroblast proliferation, diminished migratory capability, and increased collagen release. Transfection experiments indicated a substantial increase in NF-kB expression with NETs, whereas C29 led to decreased expression and release of collagen. In line, a significantly reduction in collagen content was observed in the colon of MRP8-Cre, Pad4fl/fl mice subjected to chronic DSS colitis. CONCLUSIONS: NETs potentially serve as an initial stimulus for pathological activation of fibroblasts within the intestine via the TLR2/NF-kB pathway. Given their early involvement in inflammation, inhibition of PAD4 might offer a strategy to modulate both inflammation and fibrogenesis in CD.

Intercellular interaction between FAP+ fibroblasts and CD150+ inflammatory monocytes mediates fibrostenosis in Crohn's disease.

Crohn's disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibrostenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate the mechanisms underlying fibrostenosis in CD, we analyzed the transcriptome of cells isolated from the transmural ileum of patients with CD, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from patients without CD. Our computational analysis revealed that profibrotic signals from a subset of monocyte-derived cells expressing CD150 induced a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. The transcription factor TWIST1 was identified as a key modulator of fibroblast activation and extracellular matrix (ECM) deposition. Genetic and pharmacological inhibition of TWIST1 prevents fibroblast activation, reducing ECM production and collagen deposition. Our findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibrostenosis in CD.

IL-1R signaling drives enteric glia-macrophage interactions in colorectal cancer.

Enteric glia have been recently recognized as key components of the colonic tumor microenvironment indicating their potential role in colorectal cancer pathogenesis. Although enteric glia modulate immune responses in other intestinal diseases, their interaction with the colorectal cancer immune cell compartment remains unclear. Through a combination of single-cell and bulk RNA-sequencing, both in murine models and patients, here we find that enteric glia acquire an immunomodulatory phenotype by bi-directional communication with tumor-infiltrating monocytes. The latter direct a reactive enteric glial cell phenotypic and functional switch via glial IL-1R signaling. In turn, tumor glia promote monocyte differentiation towards pro-tumorigenic SPP1+ tumor-associated macrophages by IL-6 release. Enteric glia cell abundancy correlates with worse disease outcomes in preclinical models and colorectal cancer patients. Thereby, our study reveals a neuroimmune interaction between enteric glia and tumor-associated macrophages in the colorectal tumor microenvironment, providing insights into colorectal cancer pathogenesis.

Application of Independent Component Analysis and Nelder-Mead Particle Swarm Optimization Algorithm in Non-Contact Blood Pressure Estimation.

In recent years, hypertension has become one of the leading causes of illness and death worldwide. Changes in lifestyle among the population have led to an increasing prevalence of hypertension. This study proposes a non-contact blood pressure estimation method that allows patients to conveniently monitor their blood pressure values. By utilizing a webcam to track facial features and the region of interest (ROI) for obtaining forehead images, independent component analysis (ICA) is employed to eliminate artifact signals. Subsequently, physiological parameters are calculated using the principle of optical wave reflection. The Nelder-Mead (NM) simplex method is combined with the particle swarm optimization (PSO) algorithm to optimize the empirical parameters, thus enhancing computational efficiency and accurately determining the optimal solution for blood pressure estimation. The influences of light intensity and camera distance on the experimental results are also discussed. Furthermore, the measurement time is only 10 s. The superior accuracy and efficiency of the proposed methodology are demonstrated by comparing them with those in other published literature.

Iron and ferritin effects on intensive care unit mortality: A meta-analysis.

BACKGROUND: The effect of serum iron or ferritin parameters on mortality among critically ill patients is not well characterized. AIM: To determine the association between serum iron or ferritin parameters and mortality among critically ill patients. METHODS: Web of Science, Embase, PubMed, and Cochrane Library databases were searched for studies on serum iron or ferritin parameters and mortality among critically ill patients. Two reviewers independently assessed, selected, and abstracted data from studies reporting on serum iron or ferritin parameters and mortality among critically ill patients. Data on serum iron or ferritin levels, mortality, and demographics were extracted. RESULTS: Nineteen studies comprising 125490 patients were eligible for inclusion. We observed a slight negative effect of serum ferritin on mortality in the United States population [relative risk (RR) 1.002; 95%CI: 1.002-1.004). In patients with sepsis, serum iron had a significant negative effect on mortality (RR = 1.567; 95%CI: 1.208-1.925). CONCLUSION: This systematic review presents evidence of a negative correlation between serum iron levels and mortality among patients with sepsis. Furthermore, it reveals a minor yet adverse impact of serum ferritin on mortality among the United States population.

Fibrostricturing Crohn's Disease Is Marked by an Increase in Active Eosinophils in the Deeper Layers.

INTRODUCTION: Approximately 50% of patients with Crohn's disease (CD) develop intestinal strictures necessitating surgery. The immune cell distribution in these strictures remains uncharacterized. We aimed to identify the immune cells in intestinal strictures of patients with CD. METHODS: During ileocolonic resections, transmural sections of terminal ileum were sampled from 25 patients with CD and 10 non-inflammatory bowel disease controls. Macroscopically unaffected, fibrostenotic, and inflamed ileum was collected and analyzed for immune cell distribution (flow cytometry) and protein expression. Collagen deposition was assessed through a Masson Trichrome staining. Eosinophil and fibroblast colocalization was assessed through immunohistochemistry. RESULTS: The Masson Trichrome staining confirmed augmented collagen deposition in both the fibrotic and the inflamed regions, though with a significant increased collagen deposition in the fibrotic compared with inflamed tissue. Distinct Th1, Th2, regulatory T cells, dendritic cells, and monocytes were identified in fibrotic and inflamed CD ileum compared with unaffected ileum of patients with CD as non-inflammatory bowel disease controls. Only minor differences were observed between fibrotic and inflamed tissue, with more active eosinophils in fibrotic deeper layers and increased eosinophil cationic protein expression in inflamed deeper layers. Last, no differences in eosinophil and fibroblast colocalization were observed between the different regions. DISCUSSION: This study characterized immune cell distribution and protein expression in fibrotic and inflamed ileal tissue of patients with CD. Immunologic, proteomic, and histological data suggest inflammation and fibrosis are intertwined, with a large overlap between both tissue types. However strikingly, we did identify an increased presence of active eosinophils only in the fibrotic deeper layers, suggesting their potential role in fibrosis development.

Toxicity and speciation of inorganic arsenics and their adverse effects on in vivo endpoints and oxidative stress in the marine medaka Oryzias melastigma.

Here, we investigate the effects of acute and chronic exposure to arsenate (AsV) and arsenite (AsIII) in the marine medaka Oryzias melastigma. In vivo effects, biotransformation, and oxidative stress were studied in marine medaka exposed to the two inorganic arsenics for 4 or 28 days. An investigation of embryonic development revealed no effect on in vivo parameters, but the hatching rate increased in the group exposed to AsIII. Exposure to AsIII also caused the greatest accumulation of arsenic in medaka. For acute exposure, the ratio of AsV to AsIII was higher than that of chronic exposure, indicating that bioaccumulation of inorganic arsenic can induce oxidative stress. The largest increase in oxidative stress was observed following acute exposure to AsIII, but no significant degree of oxidative stress was induced by chronic exposure. During acute exposure to AsV, the increase in the enzymatic activity of glutathione-S-transferase (GST) was twice as high compared with exposure to AsIII, suggesting that GST plays an important role in the initial detoxification process. In addition, an RNA-seq-based ingenuity pathway analysis revealed that acute exposure to AsIII may be related to cell-cycle progression. A network analysis using differentially expressed genes also revealed a potential link between the generation of inflammatory cytokines and oxidative stress due to arsenic exposure.

Postponement of total knee arthroplasties due to pandemic causes significant deterioration on patients' preoperative knee and quality of life scores.

Introduction: Elective surgeries were postponed during the COVID-19 pandemic to alleviate healthcare strains, affecting majority of elective orthopaedic surgeries such as total knee arthroplasties (TKAs). The aim of this study is to evaluate the impact on knee function and quality of life of patients who had their planned TKA postponed due to the pandemic. Methods: This is a retrospective analysis of data collected in a tertiary hospital. Patients included were diagnosed with primary knee osteoarthritis and they were initially scheduled for primary TKA between January to April 2020 but surgery was postponed by at least 6 months from the initial operative date. 160 patients were included in this study (53 males and 107 females, mean age 68.0 ± 8.1). Patients were assessed prior to initial surgery date and assessed again, prior to the postponed surgery date. Clinical scores included Knee Society Function Score (KSFS), Knee Society Knee Score (KSKS), Oxford Knee scores (OKS) and Short-Form 36 Physical and Mental Component Scores. (SF36 PCS and MCS). Paired T-test was performed for parametric data whereas Wilcoxon signed-rank analysis was performed for non-parametric data. Results: Comparing initial preoperative versus postponement preoperative scores, the cohort had significantly poorer KSKS (38.4 ± 15.4 and 36.5 ± 15.4, p = 0.034), SF36 PCS (34.3 ± 9.2 and 32.7 ± 8.6, p = 0.02) and OKS (34.9 ± 0.77 and 35.8 ± 8.6, p = 0.02) scores respectively. Conclusion: The postponement of elective TKAs has resulted in a significant deterioration of knee scores and physical quality of live scores of patients in a short span of 6 months. Further studies can evaluate if there are repercussions on long term TKAs outcomes. Level of evidence: Retrospective study, Level III.

One-Step Electrochemical Ethylene-to-Ethylene Glycol Conversion over a Multitasking Molecular Catalyst.

Ethylene glycol is an essential commodity chemical with high demand, which is conventionally produced via thermocatalytic oxidation of ethylene with huge fossil fuel consumption and CO2 emission. The one-step electrochemical approach offers a sustainable route but suffers from reliance on noble metal catalysts, low activity, and mediocre selectivity. Herein, we report a one-step electrochemical oxidation of ethylene to ethylene glycol over an earth-abundant metal-based molecular catalyst, a cobalt phthalocyanine supported on a carbon nanotube (CoPc/CNT). The catalyst delivers ethylene glycol with 100% selectivity and 1.78 min-1 turnover frequency at room temperature and ambient pressure, more competitive than those obtained over palladium catalysts. Experimental data demonstrate that the catalyst orchestrates multiple tasks in sequence, involving electrochemical water activation to generate high-valence Co-oxo species, ethylene epoxidation to afford an ethylene oxide intermediate via oxygen transfer, and eventually ring-opening of ethylene oxide to ethylene glycol facilitated by in situ formed Lewis acid site. This work offers a great opportunity for commodity chemicals synthesis based on a one-step, earth-abundant metal-catalyzed, and renewable electricity-driven route.

Single and combined effects of increased temperature and methylmercury on different stages of the marine rotifer Brachionus plicatilis.

Rapid, anthropogenic activity-induced global warming is a severe problem that not only raises water temperatures but also shifts aquatic environments by increasing the bioavailability of heavy metals (HMs), with potentially complicated effects on aquatic organisms, including small aquatic invertebrates. For this paper, we investigated the combined effects of temperature (23 and 28 °C) and methylmercury (MeHg) by measuring physiological changes, bioaccumulation, oxidative stress, antioxidants, and the mitogen-activated protein kinase signaling pathway in the marine rotifer Brachionus plicatilis. High temperature and MeHg adversely affected the survival rate, lifespan, and population of rotifers, and bioaccumulation, oxidative stress, and biochemical reactions depended on the developmental stage, with neonates showing higher susceptibility than adults. These findings demonstrate that increased temperature enhances potentially toxic effects from MeHg, and susceptibility differs with the developmental stage. This study provides a comprehensive understanding of the combined effects of elevated temperature and MeHg on rotifers. ENVIRONMENTAL IMPLICATION: Methylmercury (MeHg) is a widespread and harmful heavy metal that can induce lethal effects on aquatic organisms in even trace amounts. The toxicity of metals can vary depending on various environmental conditions. In particular, rising temperatures are considered a major factor affecting bioavailability and toxicity by changing the sensitivity of organisms. However, there are few studies on the combinational effects of high temperatures and MeHg on aquatic animals, especially invertebrates. Our research would contribute to understanding the actual responses of aquatic organisms to complex aquatic environments.

Spatiotemporal profile and ecological impacts of major and trace elements in surface sediments of marginal seas of the Arctic and Northern Pacific Oceans.

The status and ecological impacts of sedimentary elements of the marginal seas of Arctic and Northern Pacific Oceans was investigated during 2016 to 2018 by using inductively coupled plasma mass spectrometry. Industrial (0.006 mg kg-1-64.6 g kg-1), precious (0.003-43.8 mg kg-1), rare earth (0.006-112.9 mg kg-1), and heavy metal (0.009-398.9 mg kg-1) elements showed spatial variation, and temporal uniformity. The results indicated ΣREEs and light REEs enrichment compared to chondrite and heavy REEs, respectively, while nonsignificant positive and negative δCe and δEu anomalies existed, respectively. High contamination and extreme enrichment of priority control, industrial (As, Mo, Re, Sb), precious (Au, Ir, Pd, Pt, and Ru) and RE elements indicated potential moderate to high ecological and biological risks. The study highlighted the ecological importance and fragile nature of these ecosystems and calls for an urgent action to ensure sustainability of these ecosystems.

Overexpression of sirtuin 1 attenuates calcium oxalate-induced kidney injury by promoting macrophage polarization.

Sirtuin 1 (SIRT1) protein is involved in macrophage differentiation, while NOTCH signaling affects inflammation and macrophage polarization. Inflammation and macrophage infiltration are typical processes that accompany kidney stone formation. However, the role and mechanism of SIRT1 in renal tubular epithelial cell injury caused by calcium oxalate (CaOx) deposition and the relationship between SIRT1 and the NOTCH signaling pathway in this urological disorder are unclear. This study investigated whether SIRT1 promotes macrophage polarization to inhibit CaOx crystal deposition and reduce renal tubular epithelial cell injury. Public single-cell sequencing data, RT-qPCR, immunostaining approaches, and Western blotting showed decreased SIRT1 expression in macrophages treated with CaOx or exposed to kidney stones. Macrophages overexpressing SIRT1 differentiated towards the anti-inflammatory M2 phenotype, significantly inhibiting apoptosis and alleviating injury in the kidneys of mice with hyperoxaluria. Conversely, decreased SIRT1 expression in CaOx-treated macrophages triggered Notch signaling pathway activation, promoting macrophage polarization towards the pro-inflammatory M1 phenotype. Our results suggest that SIRT1 promotes macrophage polarization towards the M2 phenotype by repressing the NOTCH signaling pathway, which reduces CaOx crystal deposition, apoptosis, and damage in the kidney. Therefore, we propose SIRT1 as a potential target for preventing disease progression in patients with kidney stones.

Unveiling the unprecedented catalytic capability of micro-sized Co-ZIF-L for the thermal decomposition of RDX by 2D-structure-induced mechanism reversal.

Developing MOF-based catalysts with superior catalytic properties for the thermal decomposition of cyclotrimethylenetrinitramine (RDX) is significant for the application of novel and efficient combustion catalysts oriented to RDX-based propellants with excellent combustion performance. Herein, micro-sized Co-ZIF-L with a star-like morphology (SL-Co-ZIF-L) was found to exhibit unprecedented catalytic capability for the decomposition of RDX, which can lower the decomposition temperature of RDX by 42.9 °C and boost the heat release by 50.8%, superior to that of all the ever-reported MOFs and even ZIF-67, which has similar chemical composition but a much smaller size. In-depth mechanism study from both experimental and theoretical views reveals that the weekly interacted 2D layered structure of SL-Co-ZIF-L could activate the exothermic C-N fission pathway for the decomposition of RDX in the condensed phase, thus reversing the commonly advantageous N-N fission pathway and promoting the decomposition process in the low-temperature stage. Our study reveals the unusually superior catalytic capability of micro-sized MOF catalysts and sheds light on the rational structure design of catalysts used in micromolecule transformation reactions, typically the thermal decomposition of energetic materials.

Koumine alleviates rheumatoid arthritis by regulating macrophage polarization.

ETHNOPHARMACOLOGICAL RELEVANCE: The imbalance between M1-and M2-polarized macrophages is one of the major pathophysiological changes in RA. Therefore, targeted macrophage polarization may be an effective therapy for RA. Koumine, an alkaloid monomer with the highest content and low toxicity in Gelsemium elegans Benth., has the effect of treating RA by playing an immunomodulatory role by influencing various immune cells. However, whether koumine affects macrophage polarization in RA and the associated molecular mechanisms remain unknown. AIM OF THE STUDY: To investigate the mechanism of the anti-RA effect of koumine on macrophage polarization. MATERIALS AND METHODS: The effect of koumine on macrophage polarization was investigated in vivo and in vitro. We first explored the effects of koumine on AIA rats and detected the levels of M1/M2 macrophage polarization markers in the spleen by western blotting. Then, we explored the regulatory effect of koumine on M1/M2 macrophage polarization and the effect on the PI3K/AKT signaling pathway in vitro. Finally, we verified the effects of koumine on macrophage polarization in CIA mice. RESULTS: We found that koumine alleviated symptoms, including relieving pain, reducing joint redness and swelling in AIA rats and restoring the M1/M2 macrophage balance in vivo. Interestingly, koumine had an inhibitory effect on both M1 and M2 macrophage polarization in vitro, but it had a stronger inhibitory effect on M1 macrophage. In a mixed polarization experiment, koumine mainly inhibited M1 macrophage polarization and had an inhibitory effect on the PI3K/AKT signaling pathway. Finally, we found that koumine had therapeutic effects on CIA mice, regulated macrophage polarization and inhibited the PI3K/AKT signaling pathway. CONCLUSIONS: Our results reveal that koumine regulates macrophage polarization through the PI3K/AKT signaling pathway. This may be one of the important mechanisms of its anti-RA effect, which provides a theoretical and scientific basis for the possible clinical application of koumine.

A Longer Duration of Myelopathy Symptoms is Associated With the Lack of Intraoperative Motor Evoked Potential Improvement During Decompressive Cervical Myelopathy Surgery.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: We aim to investigate the relationship between the intraoperative motor evoked potential (MEP) signal changes during surgical treatment of cervical myelopathy with postoperative functional outcomes and determine what factors correlate with MEP signal changes. SUMMARY OF BACKGROUND DATA: Intraoperative neurophysiologic monitoring with MEP for cervical cord decompression can potentially predict postoperative neurological complications. MATERIALS AND METHODS: We prospectively collected data from 114 consecutive cervical compressive myelopathy patients who underwent decompressive cervical spine surgery. Functional outcomes were measured preoperatively and postoperatively at the 6-month mark, using the modified Japanese Orthopedic Association score. RESULTS: Among the 114 patients, 87 patients showed significant MEP improvement, 1 patient with MEP degeneration, 3 patients with no change in MEP, and 23 patients with MEP change, but which eventually returned to baseline. Univariate analysis showed that patients with MEP improvement had similar 6-month functional and Japanese Orthopedic Association scores compared with patients who did not have MEP improvement. Critically, a longer duration of symptoms was shown to have a statistically significant relationship with patients who did not have MEP improvement on univariate analysis (49.2 wk in patients with no MEP improvement compared with 34.59 wk in patients with MEP improvement, P = 0.03) but this did not translate to differences in functional outcomes. There was also no statistically significant association between the functional outcome scores and demographics, surgical, or radiologic factors. CONCLUSIONS: Our study shows that the duration of symptoms is not attributed to lower functional outcomes but is associated with a lack of MEP improvement. LEVEL OF EVIDENCE: Level III.

First evidence of meso- and microplastics on the mangrove leaves ingested by herbivorous snails and induced transcriptional responses.

Although evidence suggests the ubiquity of meso- and microplastics (MMPs) in mangrove forests, our knowledge of their bioavailability and risk on mangrove leaves is scarce. Here, we investigated MMP contamination concerning submerged mangrove leaves and herbivorous snails that mainly feed on them from the four mangrove forests located in Beibu Gulf, Guangxi Province, China. Results showed that the MMP abundance on the mangrove leaves ranged from 0.01 ± 0.00 to 0.42 ± 0.15 items cm-2, while it ranged from 0.33 ± 0.21 to 6.20 ± 2.91 items individual-1 in the snails. There were significant positive correlations between snails and leaves regarding the abundance of total MMPs and the proportions of MMPs with the same characteristics. Expanded polystyrene (EPS) that mainly derived from aquaculture rafts, accounted for a major component both on the leaves and in the snails in Shi Jiao (SJ). Both the detection frequency and percentage of larger EPS (2.00-17.50 mm) on the leaves in SJ were higher than other sites. Meanwhile, the detection frequency, abundance and percentage of larger EPS on the leaves had significant positive correlations with those of micro-EPS in the snails. These findings suggested that mangrove leaves may represent a viable pathway for MMPs to enter the herbivorous snails. Larger EPS with higher frequency of occurrence on mangrove leaves were more likely to be encountered and ingested by snail considering its opportunistic feeding behavior. In addition, 11 sensitive genes involved in the processes of metabolism, intestinal mucosal immune systems, and cellular transduction in the snails were significantly suppressed by MMP exposure, which may be potentially used as early biomarkers to indicate the biological effects of MMPs under realistic environmental conditions. Overall, this study provides novel insights into the fate, sources, and biological effects of MMPs on mangrove leaves.

[Ameliorative Effects of Cang-ai Volatile Oil on Left Ventricular Remodeling in Rats].

Objective: To evaluate with 7T cardiac magnetic resonance tissue tracking imaging (CMR-TT) the ameliorative effect of Cang-ai volatile oil (CAVO) on left ventricular remodeling (LVR) in rats induced by isoproterenol (ISO), and to make preliminary investigation into CAVO's effects on endothelial dysfunction in LVR. Methods: A total of 35 healthy male Sprague-Dawley (SD) rats were randomly assigned to two groups, the experimental group ( n=27) and the normal control group ( n=8). The rat model of LVR was established by subcutaneous injection of ISO solution at 10 mg·kg -1·d -1 at multiple sites for 10 consecutive days. After modeling was completed, the surviving rats ( n=24) in the experimental group were then randomly assigned to the blank experimental group, CAVO group, and Shexiang Baoxin pill (SXBXP) group ( n=8 in each group). Rats in each group were given via gavage the corresponding intervention medicine or an equivalent amount of normal saline solution for 28 consecutive days. At the end of modeling and intragastric intervention, 7T CMR cine sequence scanning was conducted to collect data. Then, post-processing software CVI42 was used to analyze the images and to compare and contrast the changes in the parameters of left ventricular cardiac function and myocardial strain in each group before and after the administration of the medication. The rats were sacrificed after MRI scanning, and their hearts were harvested for pathological examination. The levels of serum biochemical indicators were measured by enzyme-linked immunosorbent assay (ELISA). Results: CAVO significantly increased LV ejection fraction and overall myocardial strain parameters in LVR rats, while it decreased LV volume, mass, and serum levels of endothelial function indicators in LVR rats. In addition, pathological staining showed marked improvements in the hypertrophy, necrosis and interstitial fibrosis of cardiomyocytes. Conclusion: Through the regulation of myocardial vascular endothelial function, CAVO can significantly improve cardiac functions in LVR rats, delay the process of ventricular remodeling, and have a certain amount of protective effect on cardiac structure and function in rats.

Basolateral amygdala astrocytes modulate diabetic neuropathic pain and may be a potential therapeutic target for koumine.

BACKGROUND AND PURPOSE: New remedies are required for the treatment of diabetic neuropathic pain (DNP) due to insufficient efficacy of available therapies. Here, we used chemogenetic approaches combined with in vivo pharmacology to elucidate the role of basolateral amygdala (BLA) astrocytes in DNP pathogenesis and provide new insights into therapeutic strategies for DNP. EXPERIMENTAL APPROACH: A streptozotocin-induced DNP model was established. Designer receptors exclusively activated by designer drugs (DREADDs) were used to regulate astrocyte activity. Mechanical hyperalgesia was assessed using the electronic von Frey test. Anxiety-like behaviours were detected using open field and elevated plus maze tests. Astrocytic activity was detected by immunofluorescence, and cytokine content was determined by ELISA. KEY RESULTS: BLA astrocytes were regulated by DREADDs, and inhibition of BLA astrocytes attenuated mechanical allodynia and pain-related negative emotions in DNP rats. In contrast, temporary activation of BLA astrocytes induced allodynia without anxious behaviours in naive rats. In addition, koumine (KM) alleviated mechanical allodynia and anxiety-like behaviours in DNP rats, inhibited the activation of BLA astrocytes and suppressed the inflammatory response. Furthermore, persistent activation of BLA astrocytes through chemogenetics mimicked chronic pain, and KM alleviated the pain hypersensitivity and anxiety-like behaviours. CONCLUSION AND IMPLICATIONS: DREADDs bidirectionally regulate the activity of BLA astrocytes, which proves for the first time the role of BLA astrocyte activation in the pathogenesis of DNP and represents a novel therapeutic strategy for DNP. KM ameliorates DNP, perhaps by inhibiting the activation of BLA astrocytes and reveal KM as a potential candidate for treating DNP.