Preliminary Exploration of the Biophysical Mechanisms of Pulsed Magnetic Field-Induced Cell Permeabilization.

Pulsed magnetic field treatment can enhance cell membrane permeability, allowing large molecular substances that normally cannot pass through the cell membrane to enter the cell. This research holds significant prospects for biomedical applications. However, the mechanism underlying pulsed magnetic field-induced cell permeabilization remains unclear, impeding further progress in research related to pulsed magnetic field. Currently, hypotheses about the mechanism are struggling to explain experimental results. Therefore, this study developed a parameter-adjustable pulsed magnetic field generator and designed experiments. Starting from the widely accepted hypothesis of "induced electric fields by pulsed magnetic field," we conducted a preliminary exploration of the biophysical mechanisms underlying pulsed magnetic field-induced cell permeabilization. Finally, we have arrived at an intriguing conclusion: under the current technical parameters, the impact of the pulsed magnetic field itself is the primary factor influencing changes in cell membrane permeability, rather than the induced electric field. This conclusion holds significant implications for understanding the biophysical mechanisms behind pulsed magnetic field therapy and its potential biomedical applications.

Kellerin alleviates cerebral ischemic injury by inhibiting ferroptosis via targeting Akt-mediated transcriptional activation of Nrf2.

BACKGROUND: Ischemic stroke (IS) is characterized as a detrimental cerebrovascular disease with high mortality and disability. Ferroptosis is a novel mechanism involved in neuronal death. There is a close connection between IS and ferroptosis, and inhibiting ferroptosis may provide an effective strategy for treating IS. Our previous investigations have discovered that kellerin, the active compound of Ferula sinkiangensis K. M. Shen, possesses the capability to shield against cerebral ischemia injury. PURPOSE: Our objective is to clarify the relationship between the neuroprotective properties of kellerin against IS and its ability to modulate ferroptosis, and investigate the underlying regulatory pathway. STUDY DESIGN: We investigated the impact and mechanism of kellerin in C57BL/6 mice underwent middle cerebral artery occlusion/reperfusion (MCAO/R) as well as SH-SY5Y cells exposed to oxygen-glucose deprivation/ re-oxygenation (OGD/R). METHODS: The roles of kellerin on neurological severity, cerebral infarction and edema were investigated in vivo. The regulatory impacts of kellerin on ferroptosis, mitochondrial damage and Akt/Nrf2 pathway were explored. Molecular docking combined with drug affinity responsive target stability assay (DARTS) and cellular thermal shift assay (CETSA) were performed to analyze the potential target proteins for kellerin. RESULTS: Kellerin protected against IS and inhibited ferroptosis in vivo. Meanwhile, kellerin improved the neuronal damage caused by OGD/R and suppressed ferroptosis by inhibiting the production of mitochondrial ROS in vitro. Further we found that kellerin directly interacted with Akt and enhanced its phosphorylation, leading to the increase of Nrf2 nuclear translocation and its downstream antioxidant genes expression. Moreover, kellerin's inhibitory effect on ferroptosis and mitochondrial ROS release was eliminated by inhibiting Akt/Nrf2 pathway. CONCLUSIONS: Our study firstly demonstrates that the neuroprotective properties of kellerin against IS are related to suppressing ferroptosis through inhibiting the production of mitochondrial ROS, in which its modulation on Akt-mediated transcriptional activation of Nrf2 plays an important role. This finding shed light on the potential mechanism that kellerin exerts therapeutic effects in IS.

Anti-inflammatory effects of quinolinyl analog of resveratrol targeting TLR4 in MCAO/R ischemic stroke rat model.

BACKGROUND: Among adults, stroke is the main causes of mortality and permanent disability. Neuroinflammation is one of the main causes of stoke-mediated neuronal death. Our previous study revealed that (E)-5-(2-(Quinolin-4-yl) vinyl) benzene-1, 3-diol (RV01), a quinolinyl analog of resveratrol, inhibits microglia-induced neuroinflammation and safeguards neurons from inflammatory harm. The preventive role of RV01 in ischemic stroke and its underlying cellular mechanisms and molecular targets remain poorly understood. PURPOSE: To investigate whether RV01 alleviates ischemia-reperfusion (I/R) injury by inhibiting microglia-mediated neuroinflammation and determine the potential molecular mechanisms and targets by which RV01 inhibits the I/R-mediated microglia activation. METHODS: Rat middle cerebral artery occlusion and reperfusion (MCAO/R) and BV-2 or primary microglial cells oxygen-glucose deprivation and reperfusion (OGD/R) models were established. The neurological behavior scores, 2, 3, 5-triphenyl tetrazolium chloride staining and immunofluorescence were used to detect the neuroprotective effect of RV01 in the MCAO/R rats. In addition, the mRNA expression levels of IL-6, TNF-α, and IL-1ß were detected to reveal the antineuroinflammatory effect of RV01. Moreover, a western blot assay was performed to explore the protein expression changes in NF-κB-mediated neuroinflammation. Finally, we identified TLR4 as an RV01 target through molecular docking, drug sensitivity target stability analysis, cellular thermal shift analysis, and surface plasmon resonance techniques. RESULTS: RV01 reduced the infarct volume and neurological deficits, increased the rotarod duration, and decreased the number of rightward deflections in the MCAO/R rats. RV01 inhibited the NF-κB signaling pathway in vitro and in vivo, as demonstrated by the reduction in the transcription factor p65-mediated expression of several inflammatory factors including IL-6, TNF-α, and IL-1ß. Further studies showed that its protective effect was associated with targeting the TLR4 protein. Notably, the anti-inflammatory effect of RV01 was markedly reinforced by the TLR4 knockdown, but inhibited by the overexpression of TLR4. Results revealed that the conditioned medium derived from the RV01-treated BV-2 cells significantly decreased the OGD/R-mediated neuronal damage. CONCLUSION: Our results are the first to reveal the protective effects of RV01 on cerebral ischemia, depending on its inhibitory effect on the NF-κB pathway by targeting TLR4. RV01 could be a potential protective agent in ischemic stroke treatment.

Americanin B inhibits pyroptosis in lipopolysaccharide-induced septic encephalopathy mice through targeting NLRP3 protein.

BACKGROUND: Sepsis is considered as a severe illness due to its high mortality. Sepsis can cause septic encephalopathy, thus leading to brain injury, behavioral and cognitive dysfunction. Pyroptosis is a type of regulated cell death (RCD) and takes a crucial part in occurrence and development of sepsis. Americanin B (AMEB) is a lignan compounds, which is extracted from Vernicia fordii. In our previous study, AMEB could inhibit microglial activation in inflammatory cell model. However, the function of AMEB in septic encephalopathy mice is uncertain. It would be worthwhile to ascertain the role and mechanism of AMEB in sepsis. PURPOSE: Current study designs to certify the relationship between pyroptosis and septic encephalopathy, and investigate whether AMEB can restrain NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation and restrict pyroptosis by targeting NLRP3 in septic mice model. STUDY DESIGN: C57BL/6 mice were utilized to perform sepsis model in vivo experiments. BV-2 cell lines were used for in vitro experiments. METHODS: In vivo sepsis model was established by lipopolysaccharide (LPS) intraperitoneal injection in male C57BL/6 J mice and in vitro model was exposed by LPS plus ATP in BV-2 cells. The survival rate was monitored on the corresponding days. NLRP3, apoptosis associated Speck-like protein (ASC), caspase-1, GasderminD (GSDMD), interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) level were detected by western blotting and immunofluorescence analysis. Molecular docking, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) experiments, RNAi transfection and quantitative real-time PCR were applied to confirm the potential target of AMEB. RESULTS: The results suggested that AMEB could rise survival percentage and lighten brain injury in LPS-induced sepsis mice. In addition, AMEB could inhibit pyroptosis and the activiation of NLRP3 inflammasome. The inhibiting function of AMEB on the activiation of NLRP3 inflammasome is weakened following si-NLRP3 transfection. Moreover, AMEB exerted anti-pyroptosis effect via targeting NLRP3 protein. CONCLUSIONS: Our findings first indicate NLRP3 is an effective druggable target for septic encephalopathy related brain injury, and also provide a candidate-AMEB for the treatment of septic encephalopathy. These emerging findings on AMEB in models of sepsis suggest an innovative approach that may be beneficial in the prevention of septic encephalopathy.

Integrated network pharmacology and experimental validation-based approach to reveal the underlying mechanisms and key material basis of Jinhua Qinggan granules against acute lung injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Jinhua Qinggan granules (JHQG), the traditional Chinese formula come into the market in 2016, has been proved clinically effective against coronavirus disease. Acute lung injury (ALI) is a major complication of respiratory infection such as coronavirus and influenza virus, with a high clinical fatality rate. Macrophage activation-induced inflammatory response plays a crucial role in the pathogenesis of ALI. However, the participation of inflammatory response in the efficacy of JHQG and its material basis against ALI is still unknown. AIM OF THE STUDY: The research aims to investigate the inflammatory response-involved efficacy of JHQG on ALI, explore the "ingredient-target-pathway" mechanisms, and searching for key material basis of JHQG by integrated network pharmacology and experimental validation-based approach. MATERIALS AND METHODS: Lipopolysaccharide (LPS)-induced ALI mice was established to assess the protective impact of JHQG. Network pharmacology was utilized to identify potential targets of JHQG and investigate its action mechanisms related to inflammatory response in treating ALI. The therapeutic effect and mechanism of the primary active ingredient in JHQG was verified through high performance liquid chromatography (HPLC) and a combination of wet experiments. RESULTS: JHQG remarkably alleviated lung damage in mice model via suppressing macrophage activation, and inhibiting pro-inflammatory mediator level, p-ERK and p-STAT3 expression, TLR4/NF-κB activation. Network pharmacology combined with HPLC found luteolin is the main effective component of JHQG, and it could interact with TLR4/MD2 complex, further exerting the anti-inflammatory property and the protective role against ALI. CONCLUSIONS: In summary, our finding clarified the underlying mechanisms and material basis of JHQG therapy for ALI by integrated network pharmacology and experimental validation-based strategy.

De Novo Generation and Identification of Novel Compounds with Drug Efficacy Based on Machine Learning.

One of the main challenges in small molecule drug discovery is finding novel chemical compounds with desirable activity. Traditional drug development typically begins with target selection, but the correlation between targets and disease remains to be further investigated, and drugs designed based on targets may not always have the desired drug efficacy. The emergence of machine learning provides a powerful tool to overcome the challenge. Herein, a machine learning-based strategy is developed for de novo generation of novel compounds with drug efficacy termed DTLS (Deep Transfer Learning-based Strategy) by using dataset of disease-direct-related activity as input. DTLS is applied in two kinds of disease: colorectal cancer (CRC) and Alzheimer's disease (AD). In each case, novel compound is discovered and identified in in vitro and in vivo disease models. Their mechanism of actionis further explored. The experimental results reveal that DTLS can not only realize the generation and identification of novel compounds with drug efficacy but also has the advantage of identifying compounds by focusing on protein targets to facilitate the mechanism study. This work highlights the significant impact of machine learning on the design of novel compounds with drug efficacy, which provides a powerful new approach to drug discovery.

Sesquiterpenes from Wikstroemia lungtzeensis with anti-neuroinflammatory effects.

An anti-neuroinflammatory activities-guided phytochemical research of Wikstroemia lungtzeensis was performed for the first time. Three undescribed carotane-type sesquiterpenes, excoecafolinols C-E (1-3), and nine known sesquiterpene derivatives were isolated from the effective ethyl acetate extract of W. lungtzeensis. Their structures were determined based on multiple spectroscopic techniques and electronic circular dichroism (ECD) spectra. Furthermore, the anti-neuroinflammatory activities of the identified compounds were evaluated in lipopolysaccharide-stimulated BV-2 cells. Among them, six components (1, 2, 4, 7, 11, 12) exhibited significant inhibitory effects on nitric oxide (NO) production, with IC50 values ranging from 10.48 to 49.41 µM (positive control minocycline, IC50 53.20 µM). Carotane-type sesquiterpenes (1, 2, 4) with high content and significant inhibitory effects, are considered to be major active ingredients of W. lungtzeensis, which might serve as potential therapeutic agents for neurodegenerative diseases.

Alleviation of experimental autoimmune encephalomyelitis by transferring low RelB expression tolerogenic dendritic cells.

AIMS: Experimental autoimmune encephalomyelitis (EAE) is a widely used mouse model of multiple sclerosis. Rather than inducing immune response, tolerogenic dendritic cells (tDCs) have the ability to induce immune tolerance. In previous studies, we induced tDCs by 1,25-(OH)2D3 and 1,25-(OH)2D3 DCs significantly alleviated EAE symptoms. As downstream targets of 1,25-(OH)2D3, inhibition of RelB and MyD88 expression in DCs might induce tDCs and has therapeutic effect of MS. METHODS: Knockdown the expression of RelB and MyD88 with shRNA lentivirus to induce tDCs, adoptive transfer these tDCs to EAE mice, and investigate their therapeutic effects. RESULTS: Reduction of RelB expression induced tDCs. After transferring into EAE mice, tDCs with low RelB expression significantly alleviate their symptoms as well as reduce the immune cell infiltration and demyelination in spinal cord. CONCLUSION: RelB plays a key role in the antigen presenting function of DCs, and tDCs with low RelB expression is a potential treatment for EAE and MS.

Circum-Psoas Block versus Supra-Inguinal Fascia Iliaca Block for Postoperative Analgesia in Patients Undergoing Total Hip Arthroplasty: A Randomized Clinical Trial.

Purpose: Total hip arthroplasty (THA) is often associated with moderate to severe pain. The present study compared the efficacy of circum-psoas block (CPB) with supra-inguinal fascia iliaca block (SIFIB) for postoperative analgesia in patients undergoing THA. Patients and Methods: In this randomized trial, sixty-four patients undergoing THA were allocated randomly to the CPB group or SIFIB group with 40 mL of 0.3% ropivacaine. The primary outcome was dynamic pain score at 6 h postoperatively. Secondary outcomes included dynamic pain scores at 12, 24 and 48 h; static pain scores; sensory and motor block; opioid consumption; time to first opioid request; length of hospital stay; patient satisfaction; and adverse events. Results: CPB patients showed significantly lower dynamic pain scores at 6 (3.11 ± 0.66 vs 4.47 ± 0.74, respectively; P = 0.000), 12 (2.52 ± 0.73 vs 3.53 ± 0.85, respectively; P = 0.000) and 24 h (2.30 ± 0.57 vs 2.87 ± 0.71, respectively; P = 0.001) after surgery, as well as lower static pain scores at 6 and 12h (P = 0.001 and P = 0.033 respectively) than SIFIB patients. Lower opioid consumption was observed in the CPB group at 24 and 48 h (P = 0.000, both) than in the SIFIB group. Patients in the CPB group reported improved quadriceps strength at 6 and 12 h (P = 0.000, both), as well as better muscle strength of hip flexion at 6, 12 and 24 h (P = 0.000, P = 0.000 and P = 0.025 respectively). Compared with SIFIB, CPB was associated with increased sensory block coverage at 6, 12 and 24 h (P = 0.000, P = 0.000, and P =0.022, respectively). Conclusion: CPB has a greater potential to alleviate postoperative pain and improve recovery in THA patients than SIFIB.

Spatiotemporal gait parameter fluctuations in older adults affected by mild cognitive impairment: comparisons among three cognitive dual-task tests.

BACKGROUNDS: Gait disorder is associated with cognitive functional impairment, and this disturbance is more pronouncedly when performing additional cognitive tasks. Our study aimed to characterize gait disorders in mild cognitive impairment (MCI) under three dual tasks and determine the association between gait performance and cognitive function. METHODS: A total of 260 participants were enrolled in this cross-sectional study and divided into MCI and cognitively normal control. Spatiotemporal and kinematic gait parameters (31 items) in single task and three dual tasks (serial 100-7, naming animals and words recall) were measured using a wearable sensor. Baseline characteristics of the two groups were balanced using propensity score matching. Important gait features were filtered using random forest method and LASSO regression and further described using logistic analysis. RESULTS: After matching, 106 participants with MCI and 106 normal controls were recruited. Top 5 gait features in random forest and 4 ~ 6 important features in LASSO regression were selected. Robust variables associating with cognitive function were temporal gait parameters. Participants with MCI exhibited decreased swing time and terminal swing, increased mid stance and variability of stride length compared with normal control. Subjects walked slower when performing an extra dual cognitive task. In the three dual tasks, words recall test exhibited more pronounced impact on gait regularity, velocity, and dual task cost than the other two cognitive tests. CONCLUSION: Gait assessment under dual task conditions, particularly in words recall test, using portable sensors could be useful as a complementary strategy for early detection of MCI.

Pterostilbene participates in TLR4- mediated inflammatory response and autophagy-dependent Aß1-42 endocytosis in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD), the most prevalent form of dementia, remains untreatable. One of the factors that contributes to its progression is microglia-mediated inflammation. Pterostilbene, a compound isolated from Chinese dragon's blood, can reduce inflammation caused by overactive microglia. However, its effects on AD transgenic animals and the possible underlying mechanism remain unknown. METHODS: We evaluated the effect of pterostilbene on learning and memory difficulties in transgenic APP/PS1 mice. We used immunofluorescence to detect microglial activation and Aß aggregation. We explored the cellular mechanism of pterostilbene by establishing LPS- stimulated BV2 cells and oAß1-42- exposed HEK 293T cells that overexpress TLR4 and/or MD2 via lentivirus. We applied flow cytometry and immunoprecipitation to examine how pterostilbene regulates TLR4 signaling. RESULTS: Pterostilbene enhanced the learning and memory abilities of APP/PS1 mice and reduced microglial activation and Aß aggregation in their hippocampus. Pterostilbene alleviated oAß1-42-induced inflammation, which required the involvement of MD2. Pterostilbene disrupted the binding between TLR4 and MD2, which may further prevent TLR4 dimerization and subsequent inflammatory response. Moreover, pterostilbene restored the impaired endocytosis of oAß1-42 through an autophagy-dependent mechanism. CONCLUSION: This is the first demonstration that pterostilbene can potentially treat AD by blocking the interaction of TLR4 and MD2, thereby suppressing TLR4-mediated inflammation.

Recent Progress on Hydrogen Production from Ammonia Decomposition: Technical Roadmap and Catalytic Mechanism.

Ammonia decomposition has attracted significant attention in recent years due to its ability to produce hydrogen without emitting carbon dioxide and the ease of ammonia storage. This paper reviews the recent developments in ammonia decomposition technologies for hydrogen production, focusing on the latest advances in catalytic materials and catalyst design, as well as the research progress in the catalytic reaction mechanism. Additionally, the paper discusses the advantages and disadvantages of each method and the importance of finding non-precious metals to reduce costs and improve efficiency. Overall, this paper provides a valuable reference for further research on ammonia decomposition for hydrogen production.

Constructing Built-in Electric Field in Heterogeneous Nanowire Arrays for Efficient Overall Water Electrolysis.

Efficient bifunctional electrocatalysts for hydrogen and oxygen evolution reactions are key to water electrolysis. Herein, we report a built-in electric field (BEF) strategy to fabricate heterogeneous nickel phosphide-cobalt nanowire arrays grown on carbon fiber paper (Ni2 P-CoCH/CFP) with large work function difference (ΔΦ) as bifunctional electrocatalysts for overall water splitting. Impressively, Ni2 P-CoCH/CFP exhibits a remarkable catalytic activity for hydrogen and oxygen evolution reactions to obtain 10 mA cm-2 , respectively. Moreover, the assembled lab-scale electrolyzer driven by an AAA battery delivers excellent stability after 50 h electrocatalysis with a 100 % faradic efficiency. Computational calculations combining with experiments reveal the interface-induced electric field effect facilitates asymmetrical charge distributions, thereby regulating the adsorption/desorption of the intermediates during reactions. This work offers an avenue to rationally design high-performance heterogeneous electrocatalysts.

Olfactory function changes and the predictive performance of the Chinese Smell Identification Test in patients with mild cognitive impairment and Alzheimer's disease.

Objectives: Olfactory disorder is one of the sensory features that reflects a decline in cognitive function. However, olfactory changes and the discernibility of smell testing in the aging population have yet to be fully elucidated. Therefore, this study aimed to examine the effectiveness of the Chinese Smell Identification Test (CSIT) in distinguishing individuals with cognitive decline from those with normal aging and to determine whether the patients with MCI and AD show changes in their olfactory identification abilities. Methods: This cross-sectional study included eligible participants aged over 50 years between October 2019 and December 2021. The participants were divided into three groups: individuals with mild cognitive impairment (MCI), individuals with Alzheimer's disease (AD), and cognitively normal controls (NCs). All participants were assessed using neuropsychiatric scales, the Activity of Daily Living scale, and the 16-odor cognitive state test (CSIT) test. The test scores and the severity of olfactory impairment were also recorded for each participant. Results: In total, 366 eligible participants were recruited, including 188 participants with MCI, 42 patients with AD, and 136 NCs. Patients with MCI achieved a mean CSIT score of 13.06 ± 2.05, while patients with AD achieved a mean score of 11.38 ± 3.25. These scores were significantly lower than those of the NC group (14.6 ± 1.57; P < 0.001). An analysis showed that 19.9% of NCs exhibited mild olfactory impairment, while 52.7% of patients with MCI and 69% of patients with AD exhibited mild to severe olfactory impairment. The CSIT score was positively correlated with the MoCA and MMSE scores. The CIST score and the severity of olfactory impairment were identified as robust indicators for MCI and AD, even after adjusting for age, gender, and level of education. Age and educational level were identified as two important confounding factors that influence cognitive function. However, no significant interactive effects were observed between these confounders and CIST scores in determining the risk of MCI. The area under the ROC curve (AUC) generated from the ROC analysis was 0.738 and 0.813 in distinguishing patients with MCI and patients with AD from NCs based on the CIST scores, respectively. The optimal cutoff for distinguishing MCI from NCs was 13, and for distinguishing AD from NCs was 11. The AUC for distinguishing AD from MCI was 0.62. Conclusions: The olfactory identification function is frequently affected in patients with MCI and patients with AD. CSIT is a beneficial tool for the early screening of cognitive impairment among elderly patients with cognitive or memory issues.

Loureirin C inhibits ferroptosis after cerebral ischemia reperfusion through regulation of the Nrf2 pathway in mice.

BACKGROUND: Ischemic stroke (IS) is considered as a serious cerebral vascular disease. Ferroptosis is a novel type of regulated cell death (RCD), that closely related to the occurrence and progress of IS. Loureirin C, a type of dihydrochalcone compound derived from the Chinese Dragon's blood (CDB). The effective components extracted from CDB have shown neuroprotective effects in ischemia reperfusion models. However, the role of Loureirin C in mice after IS is not well understood. Thus, it is worth to identify the effect and mechanism of Loureirin C on IS. PURPOSE: The present research aims to prove the existence of ferroptosis in IS and explore whether Loureirin C can inhibit ferroptosis by regulating nuclear factor E2 related factor 2 (Nrf2) pathway in mice and exert neuroprotective effects on IS models. METHODS: Middle cerebral artery occlusion and reperfusion (MCAO/R) model was established to evaluate the occurrence of ferroptosis and the potential Loureirin C brain-protective effect in vivo. The analysis of free iron, glutamate content, reactive oxygen species (ROS) and lipid peroxidation levels, along with transmission electron microscope (TEM) was applied to prove the existence of ferroptosis. The function of Loureirin C on Nrf2 nuclear translocation was verified by immunofluorescence staining. In vitro, primary neurons and SH-SY5Y cells were processed with Loureirin C after oxygen and glucose deprivation-reperfusion (OGD/R). ELISA kits, western blotting, co-immunoprecipitation (Co-IP) analysis, immunofluorescence, and quantitative real-time PCR were devoted to proving the neuroprotective effects of Loureirin C on IS via regulating ferroptosis and Nrf2 pathways. RESULTS: The results showed that Loureirin C not only dramatically alleviated brain injury and inhibited neurons ferroptosis in mice after MCAO/R, but also dose-dependently reduce ROS accumulation in ferroptosis after OGD/R. Further, Loureirin C inhibits ferroptosis by activating Nrf2 pathway, and promoting nuclear translocation of Nrf2. Besides, Loureirin C increases heme oxygenase 1 (HO-1), quinone oxidoreductase 1 (NQO1) and glutathione peroxidase 4 (GPX4) content after IS. Intriguingly, the anti-ferroptosis effect of Loureirin C is weakened by Nrf2 knockdown. CONCLUSION: Our discoveries first revealed that the inhibitory action of Loureirin C on ferroptosis may greatly depend on its adjusting effect on the Nrf2 pathway, suggesting that Loureirin C could act as a novel anti-ferroptosis candidate and play a therapeutic role in IS. These novel discoveries on the role of Loureirin C on IS models reveal an innovative method that may contribute to neuroprotection for the prevention of IS.

Okanin from Coreopsis tinctoria Nutt. alleviates cognitive impairment in bilateral common carotid artery occlusion mice by regulating the miR-7/NLRP3 axis in microglia.

Cognitive impairment is the main clinical feature following stroke, and microglia-mediated inflammatory response is a major contributor to it. Coreopsis tinctoria Nutt., an edible chrysanthemum, is commonly used as a functional ingredient in healthcare beverages and food. Okanin, the main active ingredient of Coreopsis tinctoria Nutt. flower, inhibits microglial activation. However, the role of okanin in cognitive impairment following ischemic stroke is still unknown. In this study, we investigated the effect of okanin on ischemic stroke and its underlying mechanism both in vivo and in vitro. Okanin was found to attenuate cognitive impairment in bilateral common carotid artery occlusion (BCCAO) mice, inhibit neuronal loss and microglial activation, decrease NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, and increase miR-7 expression. Okanin suppressed NLRP3 inflammasome activation in oxygen-glucose deprivation (OGD) and lipopolysaccharide (LPS)-stimulated microglia by increasing miR-7 expression and inhibited microglia-induced neuronal injury. This study provides new insights into the role of okanin in ischemic stroke and shows that the miR-7/NLRP3 axis plays an important role in mediating the beneficial effects of okanin on cerebral ischemia. These findings suggest that okanin has great potential as a functional food for stroke recovery.

Impact of disease-modifying therapy on dendritic cells and exploring their immunotherapeutic potential in multiple sclerosis.

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs), which play a pivotal role in inducing either inflammatory or tolerogenic response based on their subtypes and environmental signals. Emerging evidence indicates that DCs are critical for initiation and progression of autoimmune diseases, including multiple sclerosis (MS). Current disease-modifying therapies (DMT) for MS can significantly affect DCs' functions. However, the study on the impact of DMT on DCs is rare, unlike T and B lymphocytes that are the most commonly discussed targets of these therapies. Induction of tolerogenic DCs (tolDCs) with powerful therapeutic potential has been well-established to combat autoimmune responses in laboratory models and early clinical trials. In contrast to in vitro tolDC induction, in vivo elicitation by specifically targeting multiple cell-surface receptors has shown greater promise with more advantages. Here, we summarize the role of DCs in governing immune tolerance and in the process of initiating and perpetuating MS as well as the effects of current DMT drugs on DCs. We then highlight the most promising cell-surface receptors expressed on DCs currently being explored as the viable pharmacological targets through antigen delivery to generate tolDCs in vivo.

Coordination Polymer-Mediated Molecular Surgery for Precise Interconversion of Dicyclobutane Compounds.

A Cd(II)-based coordination polymer {[Cd2(5-F-1,3-bpeb)2(FBA)4]·H2O}n (CP1) was obtained from Cd(II) salt, 5-fluoro-1,3-bis[2-(4-pyridyl)ethenyl]benzene (5-F-1,3-bpeb), and p-fluorobenzoic acid (HFBA). Within the one-dimensional chain structure of CP1, a pair of 5-F-1,3-bpeb was arranged in a face-to-face style. Upon UV irradiation and heat treatment, multiple cyclobutane isomers, including specific monocyclobutanes (1 with an endo-cyclobutane ring in CP1-1 and 1' with an exo-cyclobutane ring in CP1-1') and dicyclobutanes (endo,endo-dicyclobutane 2α in CP1-2α, exo,endo-dicyclobutane 2ß in CP1-2ß, and exo,exo-dicyclobutane 2γ in CP1-2γ) were stereoselectively produced. These isomers could be interconverted inside the CP via cutting/coupling specific bonds, which may be regarded as a type of molecular surgery. The precision of cutting/coupling relied on the thermal stability of the cyclobutanes and the alignment of the reactive alkene centers. The conversion processes were tracked through nuclear magnetic resonance, in situ powder X-ray diffraction, and IR spectroscopy. This approach can be considered as skeletal editing to construct complex organic compounds directly from one precursor.

Loureirin C ameliorates ischemia and reperfusion injury in rats by inhibiting the activation of the TLR4/NF-κB pathway and promoting TLR4 degradation.

Ischemic stroke is a leading cause of death and disability worldwide. Post-ischemia, microglia respond immediately to the alternations in neuronal activity and mediate inflammation. Toll-like receptor 4 (TLR4) plays a key role in this phenomenon. To explore the effect of loureirin C, an effective compound from Chinese Dragon's blood, on ischemic stroke, Sprague-Dawley rats were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) with/without intragastric administration of loureirin C (7, 14, and 28 mg/kg). Loureirin C alleviated MCAO/R-induced brain impairment evaluated by neurological scores (p < 0.001), brain water content (p < 0.001), and cerebral infarct volume (p = 0.001). The neuroprotective (p < 0.001) and inhibitory effects on microglial activation (p < 0.001) of loureirin C were revealed by immunofluorescence. Rescue studies with TLR4 overexpression in BV-2 microglia showed that the antiinflammatory effect of loureirin C was attributable to the inhibition of TLR4 protein expression. Moreover, co-immunoprecipitation assays showed that the binding of Triad3A, an E3 ubiquitin ligase of TLR4, was increased by loureirin C (p = 0.003). Our study demonstrates that loureirin C could be a promising therapeutic agent for the management of ischemic stroke by inhibiting microglial activation, potentially by Triad3A-mediated promotion of TLR4 ubiquitination and degradation.