Janus Flexible Device with Microcone Channels for Sampling and Analysis of Biological Microfluidics.

Controlling the spontaneous directional transport of droplets plays an important role in the application of microchemical reactions and microdroplet detection. Although the relevant technologies have been widely studied, the existing spontaneous droplet transport strategies still face problems of complex structure, single function, and poor flexibility. Inspired by the spontaneous droplet transport strategy in nature, an asymmetric wettability surface with microcone channels (AWS-MC) is prepared on a flexible fabric by combining surface modification and femtosecond laser manufacturing technology. On this surface, the capillary force and Laplace pressure induced by the wettability gradient and the geometric structure gradient drive the droplet transport from the hydrophobic surface to the hydrophilic surface. Notably, droplets in adjacent hydrophilic regions do not exchange substances even if the gap in the hydrophilic region is only 1 mm, which provides an ideal platform for numerous detections by a single drop. The droplet transport strategy does not require external energy and can adapt to the manipulation of various droplet types. Application of this surface in the blood of organisms is demonstrated. This work provides an effective method for microdroplet-directed self-transport and microdroplet detection.

Prenatal diagnosis of Silver-Russell syndrome with 8q12 deletion including the PLAG1 gene: a case report and review.

Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous disorder. A retrospective analysis predicted that the live birth prevalence of SRS in Estonia is 1:15,886 [Yakoreva et al., Eur J Hum Genet, 2019, 27(11), 1649-1658]. The most common causative genetic mechanism in the proband is loss of paternal methylation in the imprinted control region 1 (ICR1) at 11p15.5 chromosome. A few studies suggested that inherited or de novo loss-of-function alterations of the PLAG1 gene, including the whole-gene deletion and intragenic pathogenic variants, could cause a rare type of SRS. To date, less than 20 unrelated PLAG1-related SRS cases have been reported, and the clinical information about these cases is limited. We report the first prenatal case of SRS with 8q12 deletion (including the PLAG1 gene). The fetus presented with intrauterine growth retardation, small for gestational age, relative macrocephaly at birth, and a protruding forehead. Unlike classical SRS cases, the fetus had micrognathia and did not show body asymmetry. We hope that the literature review in this study provides new insights into genotype-phenotype relationships of PLAG1-related SRS.

Tumor Microenvironment Specific Regulation Ca-Fe-Nanospheres for Ferroptosis-Promoted Domino Synergistic Therapy and Tumor Immune Response.

Reactive oxygen species (ROS)-mediated emerging treatments exhibit unique advantages in cancer therapy in recent years. While the efficacy of ROS-involved tumor therapy is greatly restricted by complex tumor microenvironment (TME). Herein, a dual-metal CaO2@CDs-Fe (CCF) nanosphere, with TME response and regulation capabilities, are proposed to improve ROS lethal power by a multiple cascade synergistic therapeutic strategy with domino effect. In response to weak acidic TME, CCF will decompose, accompanied with intracellular Ca2+ upregulated and abundant H2O2 and O2 produced to reverse antitherapeutic TME. Then the exposed CF cores can act as both Fenton agent and sonosensitizer to generate excessive ROS in the regulated TME for enhanced synergistic CDT/SDT. In combination with calcium overloading, the augmented ROS induced oxidative stress will cause more severe mitochondrial damage and cellular apoptosis. Furthermore, CCF can also reduce GPX4 expression and enlarge the lipid peroxidation, causing ferroptosis and apoptosis in parallel. These signals of damage will finally initiate damage-associated molecular patterns to activate immune response and to realize excellent antitumor effect. This outstanding domino ROS/calcium loading synergistic effect endows CCF with excellent anticancer effect to efficiently eliminate tumor by apoptosis/ferroptosis/ICD both in vitro and in vivo.

Sensitivity and stability improvement on slippery surface-aggregated substrate for trace heavy metals detection using NELIBS.

The sensitive and stable detection of trace heavy metals in liquid is crucial given its profound impact on various aspects of human life. Currently, nanoparticle-enhanced laser-induced breakdown spectroscopy (NELIBS) with dried droplet method (DDM) is widely applied for heavy metals detection. Nevertheless, the coffee ring effect (CRE) in DDM affects the stability, accuracy, and sensitivity of NELIBS. Here, we developed a slippery surface-aggregated substrate (SS substrate) to suppress the CRE and enrich analytes, and form a plasmonic platform for NELIBS detection. The SS substrate was prepared by infiltrating perfluorinated lubricant into the pores of PTFE membrane. The droplet, with targeted elements and gold nanoparticles, was dried on the SS substate to form the plasmonic platform for NELIBS analysis. Then, trace heavy metal elements copper (Cu) and manganese (Mn) were analyzed by NELIBS. The results of Cu (RSD = 5.60%, LoD = 3.72 µg/L) and Mn (RSD = 7.42%, LoD = 6.37 µg/L), illustrated the CRE suppression and analytes enrichment by the SS substrate. The results verified the realization of stable, accurate and sensitive NELIBS detection. And the LoDs succeeded to reach the standard limit of China (GB/T 14848-2017). Furthermore, the results for groundwater detection (relative error: 5.92% (Cu) and 4.74% (Mn)), comparing NELIBS and inductively coupled plasma mass spectrometry (ICP-MS), validated the feasibility of the SS substrate in practical applications. In summary, the SS substrate exhibits immense potential for practical application such as water quality detection and supervision.

Flavor Chemical Research on Different Bee Pollen Varieties Using Fast E-Nose and E-Tongue Technology.

Bee pollen, derived from various plant sources, is renowned for its nutritional and bioactive properties, aroma, and taste. This study examined the bee pollen with the highest yield in China obtained from four plant species, namely Brassica campestris (Bc), Nelumbo nucifera (Nn), Camellia japonica (Cj), and Fagopyrum esculentum (Fe), using fast e-nose and e-tongue technology to analyze their flavor chemistry. Results showed substantial differences in scent profiles among the varieties, with distinct odor compounds identified for each, including n-butanol, decanal, and ethanol, in Bc, Nn, and Cj, respectively. The primary odorants in Fe consist of E-2-hexen-1-ol and (Z)-3-hexen-1-ol. Additionally, e-tongue analysis revealed seven distinct tastes in bee pollen samples: AHS, PKS, CTS, NMS, CPS, ANS, and SCS, with variations in intensity across each taste. The study also found correlations between taste components and specific odor compounds, providing insights for enhancing product quality control in bee pollen processing.

Nanomaterials-Involved Tumor-Associated Macrophages' Reprogramming for Antitumor Therapy.

Tumor-associated macrophages (TAMs) play pivotal roles in tumor development. As primary contents of tumor environment (TME), TAMs secrete inflammation-related substances to regulate tumoral occurrence and development. There are two kinds of TAMs: the tumoricidal M1-like TAMs and protumoral M2-like TAMs. Reprogramming TAMs from immunosuppressive M2 to immunocompetent M1 phenotype is considered a feasible way to improve immunotherapeutic efficiency. Notably, nanomaterials show great potential for biomedical fields due to their controllable structures and properties. There are many types of nanomaterials that exhibit great regulatory activities for TAMs' reprogramming. In this review, the recent progress of nanomaterials-involved TAMs' reprogramming is comprehensively discussed. The various nanomaterials for TAMs' reprogramming and the reprogramming strategies are summarized and introduced. Additionally, the challenges and perspectives of TAMs' reprogramming for efficient therapy are discussed, aiming to provide inspiration for TAMs' regulator design and promote the development of TAMs-mediated immunotherapy.

Collagen I protects human keratinocytes HaCaT against UVB injury via restoring PINK1/parkin-mediated mitophagy.

Collagen I is a major component of extracellular matrix in human skin, and is also widely used in a variety of skin-care products. In this study, we investigated the modulatory roles of collagen I on human immortalized keratinocytes HaCaT, especially when cells were irradiated with UVB. Interestingly, the cells grown on plates coated by molecular collagen I, but not fibrillar collagen I, acquired certain resistance against UVB damages, as shown by increased survival and reduced apoptosis. The accumulation of dysfunctional mitochondria in UVB-treated cells was attenuated by molecular collagen I-coating. Interestingly, molecular collagen I rescued the loss of mitochondrial biogenesis in cells treated with UVB. Loss of PINK1/parkin-mediated mitophagy was dominant for the accumulation of dysfunctional mitochondria after UVB irradiation. Of note, cells cultured on molecular collagen I-precoated plates exhibited reserved mitophagy after UVB irradiation, as reflected by the enhanced protein level of PINK1/parkin, increased mitochondrial ubiquitin and the co-localization of lysosomes and mitochondria. Moreover, in UVB-treated cells, inhibiting mitophagy by Cyclosporin A, or by silencing PINK1 or parkin, disturbed the resolution of mitochondrial stress and reduced the protective effect of molecular collagen I, indicating that mitophagy is pivotal for the protection of collagen I against UVB damage in keratinocytes HaCaT. Collectively, this study reveals an unexpected protective role of collagen I, which facilitates mitophagy to rescue cells under UVB irradiation, providing a new direction for clinical application of collagen products.

Changes in Diversity and Composition of Rhizosphere Bacterial and Fungal Community between Resistant and Susceptible Pakchoi under Plasmodiophora brassicae.

Plasmodiophora brassicae (P. brassicae) is a soil-born pathogen worldwide and can infect most cruciferous plants, which causes great yield decline and economic losses. It is not well known how microbial diversity and community composition change during P. brassicae infecting plant roots. Here, we employed a resistant and a susceptible pakchoi cultivar with and without inoculation with P. brassicae to analyze bacterial and fungal diversity using 16S rRNA V3-V4 and ITS_V1 regions, respectively. 16S rRNA V3-V4 and ITS_V1 regions were amplified and sequenced separately. Results revealed that both fungal and bacterial diversity increased, and composition was changed in the rhizosphere soil of the susceptible pakchoi compared with the resistant cultivar. In the four groups of R_mock, S_mock, R_10d, and S_10d, the most relatively abundant bacterium and fungus was Proteobacteria, accounting for 61.92%, 58.17%, 48.64%, and 50.00%, respectively, and Ascomycota, accounting for 75.11%, 63.69%, 72.10%, and 90.31%, respectively. A total of 9488 and 11,914 bacteria were observed uniquely in the rhizosphere soil of resistant and susceptible pakchoi, respectively, while only 80 and 103 fungi were observed uniquely in the correlated soil. LefSe analysis showed that 107 and 49 differentially abundant taxa were observed in bacteria and fungi. Overall, we concluded that different pakchoi cultivars affect microbial diversity and community composition, and microorganisms prefer to gather around the rhizosphere of susceptible pakchoi. These findings provide a new insight into plant-microorganism interactions.

Heterogeneous decision-making dynamics of threshold-switching agents on complex networks.

In the classical two-player decision-making scenario, individuals may have different tendencies to take a certain action, given that there exists a sufficient number of neighbors adopting a particular option. This is ubiquitous in many real-life contexts including traffic congestion, crowd evacuation, and minimal vertex cover problem. Under best-response dynamics, we investigate the decision-making behaviors of heterogeneous agents on complex networks. Results of the networked games are twofold: for networks of uniform degree distribution (e.g., the lattice) and fraction of the strategy is of a linear function of the threshold setting. Moreover, the equilibrium analysis is provided and the relationship between the equilibrium dynamics and the change of the threshold value is given quantitatively. Next, if the games are played on networks with non-uniform degree distribution (e.g., random regular and scale-free networks), influence of the threshold-switching will be weakened. Robust experiments indicate that it is not the value of the average degree, but the degree distribution that influences how the strategy evolves affected by the threshold settings. Our result shows that the decision-making behaviors can be effectively manipulated by tuning the parameters in the utility function (i.e., thresholds) of some agents for more regular network structures.

Comparative Transcriptome Analysis between Resistant and Susceptible Pakchoi Cultivars in Response to Downy Mildew.

Downy mildew caused by the obligate parasite Hyaloperonospora brassicae is a devastating disease for Brassica species. Infection of Hyaloperonospora brassicae often leads to yellow spots on leaves, which significantly impacts quality and yield of pakchoi. In the present study, we conducted a comparative transcriptome between the resistant and susceptible pakchoi cultivars in response to Hyaloperonospora brassicae infection. A total of 1073 disease-resistance-related differentially expressed genes were identified using a Venn diagram. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these genes were mainly involved in plant-pathogen interaction, plant hormone signal transduction, and other photosynthesis-related metabolic processes. Analysis of the phytohormone content revealed that salicylic acid increased significantly in the resistant material after inoculation with Hyaloperonospora brassicae, whereas the contents of jasmonic acid, abscisic acid, and 1-aminocyclopropane-1-carboxylic acid decreased. Exogenous salicylic acid treatment also significantly upregulated Hyaloperonospora brassicae-induced genes, which further confirmed a crucial role of salicylic acid during pakchoi defense against Hyaloperonospora brassicae. Based on these findings, we suggest that the salicylic-acid-mediated signal transduction contributes to the resistance of pakchoi to downy mildew, and PAL1, ICS1, NPR1, PR1, PR5, WRKY70, WRKY33, CML43, CNGC9, and CDPK15 were involved in this responsive process. Our findings evidently contribute to revealing the molecular mechanism of pakchoi defense against Hyaloperonospora brassicae.

Multi-objective optimization of cortical bone grinding parameters based on particle swarm optimization.

Grinding is a fundamental operation in craniotomy. Suitable grinding parameters will not only reduce force damage, but also ensure grinding efficiency. In this study, the regression equations of material removal rate and grinding force were obtained based on the theory of cortical bone grinding and full factorial test results, a multi-objective optimization based on the particle swarm algorithm was proposed for optimizing the grinding parameters: spindle speed, feed speed, and grinding depth in the grinding process. Two conflicting objectives, minimum grinding force and maximum material removal rate, were optimized simultaneously. The results revealed that the optimal grinding parameter combination and optimization results were as follows: spindle speed of 5000 rpm, feed rate of 60 mm/min, grinding depth of 0.6 mm, grinding force of 15.1 N, and material removal rate of 113.8 mm3/min. The parameter optimization result can provide theoretical guidance for selecting cortical bone grinding parameters in actual craniotomy.

Association between tea drinking and disability levels in older Chinese adults: a longitudinal analysis.

Objective: As the global population ages, disability among the elderly presents unprecedented challenges for healthcare systems. However, limited research has examined whether dietary interventions like tea consumption may alleviate and prevent disability in older adults. As an important dietary therapy, the health benefits of tea drinking have gained recognition across research disciplines. Therefore, this study aimed to investigate the association between tea drinking habits and disability levels in the elderly Chinese population. Methods: Leveraging data from the 2008 to 2018 waves of the Chinese Longitudinal Healthy Longevity Survey, we disaggregated tea drinking frequency and activities of daily living (ADL) measures and deployed fixed-effect ordered logit models to examine the tea-disability association for the first time. We statistically adjusted for potential confounders and conducted stratified analyses to assess heterogeneity across subpopulations. Results: Multivariable fixed-effect ordered logistic regression suggested tea drinking has protective effects against ADL disability. However, only daily tea drinking was associated with lower risks of basic activities of daily living (BADL) disability [odds ratio (OR) = 0.61; 95% confidence interval (CI), 0.41-0.92] and lower levels of instrumental activities of daily living (IADL) disability (OR = 0.78; 95% CI, 0.64-0.95). Stratified analyses indicated heterogeneous effects across age and income groups. Daily tea drinking protected against BADL (OR = 0.26 and OR = 0.28) and IADL disability (OR = 0.48 and OR = 0.45) for adults over 83 years old and high-income households, respectively. Conclusion: We found that drinking tea almost daily was protective against disability in elderly people, warranting further research into optimal dosages. Future studies should utilize more rigorous causal inference methods and control for confounders.

Evolutionary dynamics of N-player sender-receiver game in networks with community structure.

Network typology largely affects the evolutionary dynamics of collective behaviors in many real-world complex systems. As a conventional transmission model, the sender-receiver game paves the way to explore the evolution of honest signals between senders and receivers. In practice, the utilities of an agent often depend not only on pairwise interactions, but also on the group influence of players around them, and thus there is an urgent need for deeper theoretical modeling and investigations on individuals' non-pairwise interactions. Considering the underlying evolutionary game dynamics and multiple community network structures, we explore the evolution of honest behaviors by extending the sender-receiver game to multiple communities. With the new dynamical model of the multi-community system, we perform a stability analysis of the system equilibrium state. Our results reveal the condition to promote the evolution of honest behaviors and provide an effective method for enhancing collaboration behaviors in distributed complex systems. Current results help us to deeply understand how collective decision-making behaviors evolve, influenced by the spread of true information and misinformation in large dynamic systems.

Spontaneous Separation of Immiscible Organic Droplets on Asymmetric Wedge Channels with Hierarchical Microchannels.

Spontaneous separation of immiscible organic droplets has substantial research implications for environmental protection and resource regeneration. Compared to the widely explored separation of oil-water mixtures, there are fewer reports on separating mixed organic droplets on open surfaces due to the low surface tension differences. Efficient separation of mixed organic liquids by exploiting the rapid spontaneous transport of droplets on open surfaces remains a challenge. Here, through the fusion of inspiration from the fast droplet transport capability of Sarracenia trichome and the asymmetric wedge channel structure of shorebird beaks, this work proposes a spine with hierarchical microchannels and wedge channels (SHMW). Due to the synergistic effect of capillary force and asymmetric Laplace force, the SHMW can rapidly separate mixed organic droplets into two pure phases without requiring additional energy. In particular, the self-spreading of the oil solution on the open channel surface is utilized to amplify the surface energy difference between two droplets, and SHMW achieves the pickup of oil droplets floating on the surface of the organic solution. The maximum separation efficiency on 3-SHMW can reach 99.63%, and it can also realize the antigravity separation of mixed organic droplets with a surface tension difference as low as 0.87 mN·m-1. Furthermore, SHMW performs controllable separation, oil droplet pickup, and continuous separation and collection of mixed organic droplets. It is expected that this cooperative structure composed of hierarchical microchannels and wedge channels will be realized in resource recovery or chemical reactions in industrial production processes.

Integrated Transcriptome and Proteome Analysis Revealed the Regulatory Mechanism of Hypocotyl Elongation in Pakchoi.

Hypocotyl length is a critical determinant for the efficiency of mechanical harvesting in pakchoi production, but the knowledge on the molecular regulation of hypocotyl growth is very limited. Here, we report a spontaneous mutant of pakchoi, lhy7.1, and identified its characteristics. We found that it has an elongated hypocotyl phenotype compared to the wild type caused by the longitudinal growth of hypocotyl cells. Different light quality treatments, transcriptome, and proteomic analyses were performed to reveal the molecular mechanisms of hypocotyl elongation. The data showed that the hypocotyl length of lhy7.1 was significantly longer than that of WT under red, blue, and white lights but there was no significant difference under dark conditions. Furthermore, we used transcriptome and label-free proteome analyses to investigate differences in gene and protein expression levels between lhy7.1 and WT. At the transcript level, 4568 differentially expressed genes (DEGs) were identified, which were mainly enriched in "plant hormone signal transduction", "photosynthesis", "photosynthesis-antenna proteins", and "carbon fixation in photosynthetic organisms" pathways. At the protein level, 1007 differentially expressed proteins (DEPs) were identified and were mainly enriched in photosynthesis-related pathways. The comprehensive transcriptome and proteome analyses revealed a regulatory network of hypocotyl elongation involving plant hormone signal transduction and photosynthesis-related pathways. The findings of this study help elucidate the regulatory mechanisms of hypocotyl elongation in lhy7.1.

Prominent Josephson tunneling between twisted single copper oxide planes of Bi2Sr2-xLaxCuO6+y.

Josephson tunneling in twisted cuprate junctions provides a litmus test for the pairing symmetry, which is fundamental for understanding the microscopic mechanism of high temperature superconductivity. This issue is rekindled by experimental advances in van der Waals stacking and the proposal of an emergent d+id-wave. So far, all experiments have been carried out on Bi2Sr2CaCu2O8+x (Bi-2212) with double CuO2 planes but show controversial results. Here, we investigate junctions made of Bi2Sr2-xLaxCuO6+y (Bi-2201) with single CuO2 planes. Our on-site cold stacking technique ensures uncompromised crystalline quality and stoichiometry at the interface. Junctions with carefully calibrated twist angles around 45° show strong Josephson tunneling and conventional temperature dependence. Furthermore, we observe standard Fraunhofer diffraction patterns and integer Fiske steps in a junction with a twist angle of 45.0±0.2°. Together, these results pose strong constraints on the d or d+id-wave pairing and suggest an indispensable isotropic pairing component.

Pro­angiogenic activity of salvianolate and its potential therapeutic effect against acute cerebral ischemia.

Salvianolate (Sal) is a medicinal composition that is widely used in China for the treatment of coronary heart disease and angina pectoris. The aim of the present study was to investigate the potential macrophage-mediated pro-angiogenic effects of Sal in vitro. In addition, another aim was to explore the effects of Sal in a rat model of transient middle cerebral artery occlusion (tMCAO) along with the potential mechanism by which it promotes angiogenesis. In this study, human umbilical vein endothelial cells (HUVECs) and Raw264.7 macrophages in vitro, and a rat tMCAO model in vivo were used to detect the pro-angiogenic effect and mechanism of Sal. The results of in vitro experiments showed that the viability, migration and tube formation of HUVECs were promoted by the supernatant of Sal-treated Raw264.7 macrophages (s-Sal) but not by Sal alone. s-Sal also increased the levels of phosphorylated (p-)VEGFR-2, p-AKT and p-p38 MAPK in HUVECs while Sal alone did not. In vivo, treatment with Sal significantly reduced the cerebral infarction volume and neurological deficit scores in the rat tMCAO model. Similar to the mechanism observed in the in vitro experiments, Sal treatment upregulated the protein expression of VEGF and VEGFR-2, in addition to the phosphorylation of VEGFR-2, AKT and p38, in the brain tissues of the tMCAO model rats. In summary, the results of the present study suggest that the mechanism of Sal-mediated angiogenesis is associated with stimulation of the VEGF/VEGFR-2 signaling pathway by macrophages. This suggests the potential of Sal as a therapeutic option for the treatment of acute cerebral ischemic injury, which may act via the promotion of angiogenesis.

Drying Acoustically Levitated Droplets as Signal-Amplifying Platforms for Ultrasensitive and Multimode Laser Sensing.

Ultrasensitive sensing to trace atomic and molecular analytes has gained interest for its intimate relation to industrial sectors and human lives. One of the keys to ultrasensitive sensing for many analytical techniques lies in enriching trace analytes onto well-designed substrates. However, the coffee ring effect, nonuniform distribution of analytes onto substrates, in the droplet drying process hinders the ultrasensitive and stable sensing onto the substrates. Here, we propose a substrate-free strategy to suppress the coffee ring effect, enrich analytes, and self-assemble a signal-amplifying (SA) platform for multimode laser sensing. The strategy involves acoustically levitating and drying a droplet, mixed with analytes and core-shell Au@SiO2 nanoparticles, to self-assemble an SA platform. The SA platform with a plasmonic nanostructure can dramatically enrich analytes, enabling enormous spectroscopic signal amplification. Specifically, the SA platform can promote atomic detection (cadmium and chromium) to the 10-3 mg/L level by nanoparticle-enhanced laser-induced breakdown spectroscopy and can promote molecule detection (rhodamine 6G) to the 10-11 mol/L level by surface-enhanced Raman scattering. All in all, the SA platform, self-assembled by acoustic levitation, can intrinsically suppress the coffee ring effect and enrich trace analytes, enabling ultrasensitive multimode laser sensing.

Multi-pathway neuroprotective effects of a novel salidroside derivative SHPL-49 against acute cerebral ischemic injury.

SHPL-49 ((2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(4-(4-methoxyphenyl) butoxy) tetrahydro-2H-pyran-3,4,5-triol) is a novel glycoside derivative obtained from structural modification of salidroside, which is isolated from the medicinal plant Rhodiola rosea L. SHPL-49 was administered to rats with permanent middle cerebral artery occlusion (pMCAO) for 5 days, and it was found that SHPL-49 could alleviate the cerebral infarct volume and reduce the neurological deficit score. Moreover, the effective time window of SHPL-49 in the pMCAO model was from 0.5 to 8 h after embolization. In addition, the result of immunohistochemistry showed that SHPL-49 could increase the number of neurons in the brain tissue and reduce the occurrence of apoptosis. Morris water maze and Rota-rod experiments showed that SHPL-49 could improve neurological deficits, repair neurocognitive and motor dysfunction, and enhance learning and memory ability in the pMCAO model after 14 days of SHPL-49 treatment. Further in vitro experiments showed that SHPL-49 significantly reduced the calcium overload of PC-12 cells and the production of reactive oxygen species (ROS) induced by oxygen and glucose deprivation (OGD), and increased the levels of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), decreased the production of malondialdehyde (MDA). Furthermore, SHPL-49 could reduce cell apoptosis by increasing protein expression ratio of anti-apoptotic factor Bcl-2 to pro-apoptotic factor Bax in vitro. SHPL-49 also regulated the expression of Bcl-2 and Bax in ischemic brain tissue, and even inhibited the caspase cascade of pro-apoptotic proteins Cleaved-caspase 9 and Cleaved-caspase 3. Taken together, SHPL-49 exhibited neuroprotective effects against cerebral ischemic injury through multiple pathways, such as alleviating calcium overload, reducing oxidative stress damage, and inhibiting apoptosis.

The antinociceptive activity and mechanism of action of cannabigerol.

Cannabis has been used for centuries to treat pain. The antinociceptive activity of tetrahydrocannabinol (THC) or cannabidiol (CBD) has been widely studied. However, the antinociceptive effects of other cannabis components, such as cannabichromene (CBC) and cannabigerol (CBG), have rarely been revealed. The antinociceptive mechanism of CBG is not yet clear, so we investigated the antinociceptive effect of CBG on different pain models, and explored the mechanism of action of CBG to exert antinociceptive effects. In the current study, we compared the antinociceptive effects of CBC, CBD, and CBG on the carrageenan-induced inflammatory pain model in mice, and the results showed that CBG had a better antinociceptive effects through intraplantar administration. On this basis, we further investigated the antinociceptive effect of CBG on CIA-induced arthritis pain model and nerve pain model in mice, and found that CBG also relieved on both types of pain. Then, we explored the antinociceptive mechanism of CBG, which revealed that CBG can activate TRPV1 and desensitize it to block the transmission of pain signals. In addition, CBG can further activate CB2R, but not CB1R, to stimulate the release of ß-endorphin, which greatly promotes the antinociceptive effect. Finally, the safety test results showed that CBG had no irritating effect on the rabbits' skin, and it did not induce significant biochemical and hematological changes in mice. Transdermal delivery results also indicated that CBG has certain transdermal properties. Overall, this study indicates that CBG is promising for developing a transdermal dosage for pain management.