Can cerebellar theta-burst stimulation improve balance function and gait in stroke patients? A randomized controlled trial.

BACKGROUND: The cerebellum is a key structure involved in balance and motor control, and has become a new stimulation target in brain regulation technology. Interference theta-burst simulation (iTBS) is a novel simulation mode of repetitive transcranial magnetic simulation. However, the impact of cerebellar iTBS on balance function and gait in stroke patients is still unknown. AIM: The aim of this study was to determine whether cerebellar iTBS can improve function, particularly balance and gait, in patients with post-stroke hemiplegia. DESIGN: This study is a randomized, double-blind, sham controlled clinical trial. SETTING: The study was carried out at the Department of Rehabilitation Medicine in a general hospital. POPULATION: Patients with stroke with first unilateral lesions were enrolled in the study. METHODS: Thirty-six patients were randomly assigned to the cerebellar iTBS group or sham stimulation group. The cerebellar iTBS or pseudo stimulation site is the ipsilateral cerebellum on the paralyzed side, which is completed just before daily physical therapy. The study was conducted five times a week for two consecutive weeks. All patients were assessed before the intervention (T0) and at the end of 2 weeks of treatment (T1), respectively. The primary outcome was the Berg Balance Scale (BBS), while secondary outcome measures included the Fugl Meyer Lower Limb Assessment Scale (FMA-LE), timed up and go (TUG), Barthel Index (BI), and gait analysis. RESULTS: After 2 weeks of intervention, the BBS, FMA-LE, TUG, and BI score in both the iTBS group and the sham group were significantly improved compared to the baseline (all P<0.05). Also, there was a significant gait parameter improvement including the cadence, stride length, velocity, step length compared to the baseline (P<0.05) in the iTBS group, but only significant improvement in cadence was identified in the sham group (P<0.05). Intergroup comparison showed that the BBS (P<0.001), FMA-LE (P<0.001), and BI (P=0.002) in the iTBS group were significantly higher than those in the sham group, and the TUG in the iTBS was significantly lower than that in the sham group (P=0.002). In addition, there were significant differences in cadence (P=0.029), strip length (P=0.046), gain velocity (P=0.002), and step length of affected lower limb (P=0.024) between the iTBS group and the sham iTBS group. CONCLUSIONS: Physical therapy is able to improve the functional recovery in hemiplegic patients after stroke, but the cerebellar iTBS can facilitate and accelerate the recovery, particularly the balance function and gait. Cerebellar iTBS could be an efficient and facilitative treatment for patients with stroke. CLINICAL REHABILITATION IMPACT: Cerebellar iTBS provides a convenient and efficient treatment modality for functional recovery of patients with stroke, especially balance function and gait.

Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive Gs signaling.

Many orphan G protein-coupled receptors (GPCRs) remain understudied because their endogenous ligands are unknown. Here, we show that a group of class A/rhodopsin-like orphan GPCRs including GPR61, GPR161 and GPR174 increase the cAMP level similarly to fully activated D1 dopamine receptor (D1R). We report cryo-electron microscopy structures of the GPR61‒Gs, GPR161‒Gs and GPR174‒Gs complexes without any exogenous ligands. The GPR174 structure reveals that endogenous lysophosphatidylserine (lysoPS) is copurified. While GPR174 fails to respond to exogenous lysoPS, likely owing to its maximal activation by the endogenous ligand, GPR174 mutants with lower ligand binding affinities can be specifically activated by lysoPS but not other lipids, in a dose-dependent manner. Moreover, GPR174 adopts a non-canonical Gs coupling mode. The structures of GPR161 and GPR61 reveal that the second extracellular loop (ECL2) penetrates into the orthosteric pocket, possibly contributing to constitutive activity. Our work definitively confirms lysoPS as an endogenous GPR174 ligand and suggests that high constitutive activity of some orphan GPCRs could be accounted for by their having naturally abundant ligands.

Global trends and performances in diabetic retinopathy studies: A bibliometric analysis.

Objective: The objective of this study is to conduct a comprehensive bibliometric analysis to identify and evaluate global trends in diabetic retinopathy (DR) research and visualize the focus and frontiers of this field. Methods: Diabetic retinopathy-related publications from the establishment of the Web of Science (WOS) through 1 November 2022 were retrieved for qualitative and quantitative analyses. This study analyzed annual publication counts, prolific countries, institutions, journals, and the top 10 most cited literature. The findings were presented through descriptive statistics. VOSviewer 1.6.17 was used to exhibit keywords with high frequency and national cooperation networks, while CiteSpace 5.5.R2 displayed the timeline and burst keywords for each term. Results: A total of 10,709 references were analyzed, and the number of publications continuously increased over the investigated period. America had the highest h-index and citation frequency, contributing to the most influence. China was the most prolific country, producing 3,168 articles. The University of London had the highest productivity. The top three productive journals were from America, and Investigative Ophthalmology Visual Science had the highest number of publications. The article from Gulshan et al. (2016; co-citation counts, 2,897) served as the representative and symbolic reference. The main research topics in this area were incidence, pathogenesis, treatment, and artificial intelligence (AI). Deep learning, models, biomarkers, and optical coherence tomography angiography (OCTA) of DR were frontier hotspots. Conclusion: Bibliometric analysis in this study provided valuable insights into global trends in DR research frontiers. Four key study directions and three research frontiers were extracted from the extensive DR-related literature. As the incidence of DR continues to increase, DR prevention and treatment have become a pressing public health concern and a significant area of research interest. In addition, the development of AI technologies and telemedicine has emerged as promising research frontiers for balancing the number of doctors and patients.

The screening for marine fungal strains with high potential in alkaloids production by in situ colony assay and LC-MS/MS based secondary metabolic profiling.

Background: Alkaloids are the second primary class of secondary metabolites (SMs) from marine organisms, most of which have antioxidant, antitumor, antibacterial, anti-inflammatory, and other activities. However, the SMs obtained by traditional isolation strategies have drawbacks such as highly reduplication and weak bioactivity. Therefore, it is significantly important to establish an efficient strategy for screening strains and mining novel compounds. Methods: In this study, we utilized in situ colony assay combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify the strain with high potential in alkaloids production. The strain was identified by genetic marker genes and morphological analysis. The secondary metabolites from the strain were isolated by the combine use of vacuum liquid chromatography (VLC), ODS column chromatography, and Sephadex LH-20. Their structures were elucidated by 1D/2D NMR, HR-ESI-MS, and other spectroscopic technologies. Finally, these compounds bioactivity were assay, including anti-inflammatory and anti-ß aggregation. Results: Eighteen marine fungi were preliminarily screened for alkaloids production by in situ colony assay using Dragendorff reagent as dye, and nine of them turned orange, which indicated abundant alkaloids. By thin-layer chromatography (TLC), LC-MS/MS, and multiple approaches assisted Feature-Based Molecular Networking (FBMN) analysis of fermentation extracts, a strain ACD-5 (Penicillium mallochii with GenBank accession number OM368350) from sea cucumber gut was selected for its diverse alkaloids profiles especially azaphilones. In bioassays, the crude extracts of ACD-5 in Czapek-dox broth and brown rice medium showed moderate antioxidant, acetylcholinesterase inhibitory, anti-neuroinflammatory, and anti-ß aggregation activities. Three chlorinated azaphilone alkaloids, compounds 1-3 (sclerotioramine, isochromophilone VI, and isochromophilone IX, respectively), were isolated from the fermentation products of ACD-5 in brown rice medium guided by bioactivities and mass spectrometry analysis. Compound 1 had shown remarkable anti-neuroinflammatory activity in liposaccharide induced BV-2 cells. Conclusion: In summary, in situ colony screening together with LC-MS/MS, multi-approach assisted FBMN can act as an efficient screening method for strains with potential in alkaloids production.

A 3D-printed PCL/PEI/DNA bioactive scaffold for chemotherapy drug capture in vivo.

Systemic chemotherapy after surgery is necessary to control tumor recurrence, but the severe side effects caused by chemotherapeutic drugs pose a great threat to patients' health. In this study, we originally develop a porous scaffold used for chemotherapy drug capture by using 3D printing technology. The scaffold is mainly composed of poly (ε-caprolactone) (PCL) and polyetherimide (PEI) with a mass ratio of 5/1. Subsequently, the printed scaffold is modified with DNA through the strong electrostatic integration between DNA and PEI to endow the scaffold with the specific absorption to doxorubicin (DOX, a widely used chemotherapy drug). The results show that pore diameter has an important influence on DOX adsorption, and smaller pores will ensure a higher DOX absorption. In vitro, the printed scaffold can absorb about 45 % DOX. While in vivo, it remains a higher absorption ability to DOX when the scaffold is successfully implanted into the common jugular vein of rabbits. What's more, the scaffold has good hemocompatibility and biocompatibility, indicating its safety for in vivo application. Taken together, the 3D-printed scaffold with excellent capture of chemotherapy drugs will play an important role in reducing the toxic side effects of chemotherapy drugs and improving the life quality of patients.

Land use intensity controls the diversity-productivity relationship in northern temperate grasslands of China.

Introduction: The diversity-productivity relationship is a central issue in maintaining the grassland ecosystem's multifunctionality and supporting its sustainable management. Currently, the mainstream opinion on the diversity-productivity relationship recognizes that increases in species diversity promote ecosystem productivity. Methods: Here, we challenge this opinion by developing a generalized additive model-based framework to quantify the response rate of grassland productivity to plant species diversity using vegetation survey data we collected along a land-use intensity gradient in northern China. Results: Our results show that the grassland aboveground biomass responds significantly positively to the Shannon-Wiener diversity index at a rate of 46.8 g m-2 per unit increase of the Shannon-Wiener index in enclosure-managed grasslands, under the co-influence of climate and landscape factors. The aboveground biomass response rate stays positive at a magnitude of 47.1 g m-2 in forest understory grassland and 39.7 g m-2 in wetland grassland. Conversely, the response rate turns negative in heavily grazed grasslands at -55.8 g m-2, transiting via near-neutral rates of -7.0 and -7.3 g m-2 in mowing grassland and moderately grazed grassland, respectively. Discussion: These results suggest that the diversity-productivity relationship in temperate grasslands not only varies by magnitude but also switches directions under varying levels of land use intensity. This highlights the need to consider land use intensity as a more important ecological integrity indicator for future ecological conservation programs in temperate grasslands.

Sown alfalfa pasture decreases grazing intensity while increasing soil carbon: Experimental observations and DNDC model predictions.

Introduction: Grasslands are the most important land use in China and have experienced extensive degradation in the past few decades due to overgrazing. However, regionally viable solutions to grazing intensity alleviation remained elusive to date. Methods: Here, we evaluated the grazing intensity effects of sown alfalfa pastures in northern China using an experiment-modeling combined approach that involved six sites in field experiments and five provinces in DNDC modeling of sown alfalfa pasture's forage production and carbon sequestration potentials in marginal lands. Results: Our results showed that the sown alfalfa pasture's dry-matter yield varied between 4.5 and 9.0 Mg ha-1 under rainfed and irrigated conditions, respectively, from 2025 to 2035. If half of the available marginal lands were mobilized for alfalfa forage production, these yield levels meant that livestock grazing intensity on natural grasslands may drop 8-13% under rainfed and 20-33% under irrigated conditions. Our results also showed that marginal land's soil organic carbon contents were systematically higher under sown alfalfa pasture than under fallow management by a big margin of 8.5 and 9.9 g kg-1 (i.e., +79 and +95%), under rainfed and irrigated conditions, respectively, during 2025-2035. Discussion: Overall, these results demonstrated that sown alfalfa pasture on marginal lands represents an effective grassland conservation pathway over the short- to medium-term time horizon based on current technologies.

Achieving the dual goals of biomass production and soil rehabilitation with sown pasture on marginal cropland: Evidence from a multi-year field experiment in Northeast Inner Mongolia.

Grassland is the primary land use in China but has experienced severe degradation in recent decades due to overgrazing and conversion to agricultural production. Here, we conducted a field experiment in northeastern Inner Mongolia to test the effectiveness of sown pastures in lowering the grazing pressure on grasslands and raising the quality of marginal soils. Alfalfa and smooth bromegrass monocultures and mixture were sown in a marginal cropland field in Hulunber in June 2016. Biomass productivity, soil physicochemical, and biological properties were monitored annually from 2016 to 2020. The results showed that the marginal cropland soil responded consistently positively to sown pastures for major soil properties. Soil organic carbon (SOC) and total nitrogen (TN) increased by 48 and 21%, respectively, from 2016 to 2020 over the 0-60 cm soil depth range. Soil microbes responded proactively too. The soil microbial biomass C (SMBC) and N (SMBN) increased by 117 and 39%, respectively, during the period of 2016-2020. However, by the end of the experiment, the soil of a natural grassland field, which was included in the experiment as a control, led the sown pasture soil by 28% for SOC, 35% for TN, 66% for SMBC, and 96% for SMBN. Nevertheless, the natural grassland soil's productive capacity was inferior to that of the sown pasture soil. The average aboveground biomass productivity of sown pastures was measured at 8.4 Mg ha-1 in 2020, compared to 5.0 Mg ha-1 for natural grassland, while the root biomass of sown pastures was averaged at 7.5 Mg ha-1, leading the natural grassland by 15%. Our analyses also showed that the sown pastures' biomass productivity advantage had a much-neglected potential in natural grassland protection. If 50% of the available marginal cropland resources in Hulunber under the current environmental protection law were used for sown pastures, the livestock grazing pressure on the natural grasslands would decrease by a big margin of 38%. Overall, these results represent systematic empirical and analytical evidence of marginal cropland soil's positive responses to sown pastures, which shows clearly that sown pasture is a valid measure both for soil rehabilitation and biomass production.

Research into the biological differences and targets in lung cancer patients with diverse immunotherapy responses.

Background: Immunotherapy has gradually become an important therapy option for lung cancer patients. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were responsible for all the public data. Results: In our study, we firstly identified 22 characteristic genes of NSCLC immunotherapy response using the machine learning algorithm. Molecule subtyping was then conducted and two patient subtypes were identified Cluster1 and Cluster2. Results showed that Cluster1 patients had a lower TIDE score and were more sensitive to immunotherapy in both TCGA and combined GEO cohorts. Biological enrichment analysis showed that pathways of epithelial-mesenchymal transition (EMT), apical junction, KRAS signaling, myogenesis, G2M checkpoint, E2F targets, WNT/ß-catenin signaling, hedgehog signaling, hypoxia were activated in Cluster2 patients. Genomic instability between Cluster1 and Cluster2 patients was not significantly different. Interestingly, we found that female patients were more adaptable to immunotherapy. Biological enrichment revealed that compared with female patients, pathways of MYC target, G2M checkpoints, mTORC1 signaling, MYC target, E2F target, KRAS signaling, oxidative phosphorylation, mitotic spindle and P53 pathway were activated. Meanwhile, monocytes might have a potential role in affecting NSCLC immunotherapy and underlying mechanism has been explored. Finally, we found that SEC14L3 and APCDD1L were the underlying targets affecting immunotherapy, as well as patients survival. Conclusions: These results can provide direction and guidance for future research focused on NSCLC immunotherapy.

Hizikia fusiforme functional oil (HFFO) prevents neuroinflammation and memory deficits evoked by lipopolysaccharide/aluminum trichloride in zebrafish.

Background: Oxidative stress, cholinergic deficiency, and neuroinflammation are hallmarks of most neurodegenerative disorders (NDs). Lipids play an important role in brain development and proper functioning. Marine-derived lipids have shown good memory-improving potentials, especially those from fish and microalgae. The cultivated macroalga Hizikia fusiforme is healthy food and shows benefits to memory, but the study is rare on the brain healthy value of its oil. Previously, we had reported that the Hizikia fusiforme functional oil (HFFO) contains arachidonic acid, 11,14,17-eicosatrienoic acid, phytol, and other molecules displaying in vitro acetylcholinesterase inhibitory and nitroxide scavenging activity; however, the in vivo effect remains unclear. In this study, we further investigated its potential effects against lipopolysaccharides (LPS)- or aluminum trichloride (AlCl3)-induced memory deficiency in zebrafish and its drug-related properties in silica. Methods: We established memory deficit models in zebrafish by intraperitoneal (i.p.) injection of lipopolysaccharides (LPS) (75 ng) or aluminum trichloride (AlCl3) (21 µg), and assessed their behaviors in the T-maze test. The interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), acetylcholine (ACh), and malondialdehyde (MDA) levels were measured 24 h after the LPS/AlCl3 injection as markers of inflammation, cholinergic activity, and oxidative stress. Furthermore, the interaction of two main components, 11,14,17-eicosatrienoic acid and phytol, was investigated by molecular docking, with the important anti-inflammatory targets nuclear factor kappa B (NF-κB) and cyclooxygenase 2 (COX-2). Specifically, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of HFFO were studied by ADMETlab. Results: The results showed that HFFO reduced cognitive deficits in zebrafish T-maze induced by LPS/AlCl3. While the LPS/AlCl3 treatment increased MDA content, lowered ACh levels in the zebrafish brain, and elevated levels of central and peripheral proinflammatory cytokines, these effects were reversed by 100 mg/kg HFFO except for MDA. Moreover, 11,14,17-eicosatrienoic acid and phytol showed a good affinity with NF-κB, COX-2, and HFFO exhibited acceptable drug-likeness and ADMET profiles in general. Conclusion: Collectively, this study's findings suggest HFFO as a potent neuroprotectant, potentially valuable for the prevention of memory impairment caused by cholinergic deficiency and neuroinflammation.

Enclosure in Combination with Mowing Simultaneously Promoted Grassland Biodiversity and Biomass Productivity.

Grassland is the primary land use in China, which has experienced extensive degradation in recent decades due to overexploitation. Here, we conducted field experiments to quantify the degraded grassland's recovery rate in Northeast Inner Mongolia in response to restoration measures, including fallow + enclosure (FE) and mowing + enclosure (ME) in comparison to livestock grazing (LG), since 2005. Plant community properties were surveyed and aboveground biomass (AGB) sampled in summer 2013. Our results showed that the regional dominant species Leymus chinensis retained its dominance under FE, whereas a range of forb species gained dominance under LG. Vegetative cover was maximal under FE and minimal under LG. The least amount of vegetation development and AGB were observed under LG. However, plant diversity showed an opposite pattern, with maximal diversity under LG and minimal under FE. Statistical analysis revealed that AGB was negatively associated with plant diversity for all treatments except ME. For ME, a positive AGB-diversity relationship was characterized, suggesting that mowing intensity was a controlling factor for the AGB-diversity relationship. Overall, these results demonstrated that enclosure plus mowing represented an effective conservation measure that provided fair support to forage production and a progressive pathway to a more resilient grassland system.

Ligand recognition and biased agonism of the D1 dopamine receptor.

Dopamine receptors are widely distributed in the central nervous system and are important therapeutic targets for treatment of various psychiatric and neurological diseases. Here, we report three cryo-electron microscopy structures of the D1 dopamine receptor (D1R)-Gs complex bound to two agonists, fenoldopam and tavapadon, and a positive allosteric modulator LY3154207. The structure reveals unusual binding of two fenoldopam molecules, one to the orthosteric binding pocket (OBP) and the other to the extended binding pocket (EBP). In contrast, one elongated tavapadon molecule binds to D1R, extending from OBP to EBP. Moreover, LY3154207 stabilizes the second intracellular loop of D1R in an alpha helical conformation to efficiently engage the G protein. Through a combination of biochemical, biophysical and cellular assays, we further show that the broad conformation stabilized by two fenoldopam molecules and interaction between TM5 and the agonist are important for biased signaling of D1R.

Circ_0064288 acts as an oncogene of hepatocellular carcinoma cells by inhibiting miR-335-5p expression and promoting ROCK1 expression.

BACKGROUND: Reportedly, circular RNA (circRNA) is a key modulator in the development of human malignancies. This work is aimed to probe the expression pattern, biological effects and mechanism of circ_0064288 on hepatocellular carcinoma (HCC) progression. METHODS: The differentially expressed circRNA was screened by analyzing the expression profiles of circRNAs in HCC tissues and normal tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to examine the expression of circ_0064288, miR-335-5p and Rho associated coiled-coil containing protein kinase 1 (ROCK1) mRNA in HCC specimens. After circ_0064288 was overexpressed or knocked down in HCC cells, cell growth was detected by the CCK-8 experiment, and cell migration was evaluated using Transwell experiment and scratch healing experiment. The targeting relationship between miR-335-5p and circ_0064288 and ROCK1 mRNA was predicted and verified using bioinformatic analysis and dual-luciferase reporter gene experiments, respectively. Western blot was executed to examine ROCK1 protein expression in HCC cells. RESULTS: Circ_0064288 and ROCK1 expression was up-modulated in HCC, while miR-335-5p was down-modulated. High circ_0064288 expression was associated with shorter survival time of HCC patients. It was also revealed that circ_0064288 overexpression remarkably enhanced HCC cell growth and migration, while knockdown of circ_0064288 induced opposite effects. Additionally, circ_0064288 could competitively bind with miR-335-5p thereby up-modulate ROCK1 expression. MiR-335-5p overexpression partly counteracted the effect of circ_0064288 overexpression on HCC cells. CONCLUSION: Circ_0064288 facilitates HCC cell growth and migration by modulating the miR-335-5p/ROCK1 axis.

Marine fungal metabolite butyrolactone I prevents cognitive deficits by relieving inflammation and intestinal microbiota imbalance on aluminum trichloride-injured zebrafish.

BACKGROUND: Mounting evidences indicate that oxidative stress, neuroinflammation, and dysregulation of gut microbiota are related to neurodegenerative disorders (NDs). Butyrolactone I (BTL-I), a marine fungal metabolite, was previously reported as an in vitro neuroprotectant and inflammation inhibitor. However, little is known regarding its in vivo effects, whereas zebrafish (Danio rerio) could be used as a convenient in vivo model of toxicology and central nervous system (CNS) diseases. METHODS: Here, we employed in vivo and in silico methods to investigate the anti-NDs potential of BTL-I. Specifically, we established a cognitive deficit model in zebrafish by intraperitoneal (i.p.) injection of aluminum trichloride (AlCl3) (21 µg) and assessed their behaviors in the T-maze test. The proinflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) as well as acetylcholinesterase (AChE) activity or glutathione (GSH) levels were assayed 24 h after AlCl3 injection. The intestinal flora variation of the zebrafish was investigated by 16S rDNA high-throughput analysis. The marine fungal metabolite, butyrolactone I (BTL-I), was used to modulate zebrafish cognitive deficits evoked by AlCl3 and evaluated about its effects on the above inflammatory, cholinergic, oxidative stress, and gut floral indicators. Furthermore, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of BTL-I were studied by the in silico tool ADMETlab. RESULTS: BTL-I dose-dependently ameliorated AlCl3-induced cognitive deficits in zebrafish. While AlCl3 treatment elevated the levels of central and peripheral proinflammatory cytokines, increased AChE activity, and lowered GSH in the brains of zebrafish, these effects, except GSH reduction, were reversed by 25-100 mg/kg BTL-I administration. Besides, 16S rDNA high-throughput sequencing of the intestinal flora of zebrafish showed that AlCl3 decreased Gram-positive bacteria and increased proinflammatory Gram-negative bacteria, while BTL-I contributed to maintaining the predominance of beneficial Gram-positive bacteria. Moreover, the in silico analysis indicated that BTL-I exhibits acceptable drug-likeness and ADMET profiles. CONCLUSIONS: The present findings suggest that BTL-I is a potential therapeutic agent for preventing CNS deficits caused by inflammation, neurotoxicity, and gut flora imbalance.

Endocannabinoid activation of the TRPV1 ion channel is distinct from activation by capsaicin.

Transient receptor potential vanilloid 1 (TRPV1) ion channel serves as the detector for noxious temperature above 42 °C, pungent chemicals like capsaicin, and acidic extracellular pH. This channel has also been shown to function as an ionotropic cannabinoid receptor. Despite the solving of high-resolution three-dimensional structures of TRPV1, how endocannabinoids such as anandamide and N-arachidonoyl dopamine bind to and activate this channel remains largely unknown. Here we employed a combination of patch-clamp recording, site-directed mutagenesis, and molecular docking techniques to investigate how the endocannabinoids structurally bind to and open the TRPV1 ion channel. We found that these endocannabinoid ligands bind to the vanilloid-binding pocket of TRPV1 in the "tail-up, head-down" configuration, similar to capsaicin; however, there is a unique interaction with TRPV1 Y512 residue critical for endocannabinoid activation of TRPV1 channels. These data suggest that a differential structural mechanism is involved in TRPV1 activation by endocannabinoids compared with the classic agonist capsaicin.

Molecular mechanism underlying modulation of TRPV1 heat activation by polyols.

Sensing noxiously high temperatures is crucial for living organisms to avoid heat-induced injury. The TRPV1 channel has long been known as a sensor for noxious heat. However, the mechanism of how this channel is activated by heat remains elusive. Here we found that a series of polyols including sucrose, sorbitol, and hyaluronan significantly elevate the heat activation threshold temperature of TRPV1. The modulatory effects of these polyols were only observed when they were perfused extracellularly. Interestingly, mutation of residues E601 and E649 in the outer pore region of TRPV1 largely abolished the effects of these polyols. We further observed that intraplantar injection of polyols into the hind paws of rats reduced their heat-induced pain response. Our observations not only suggest that the extracellular regions of TRPV1 are critical for the modulation of heat activation by polyols, but also indicate a potential role of polyols in reducing heat-induced pain sensation.

MiR-96 promotes myocardial infarction-induced apoptosis by targeting XIAP.

Acute myocardial infarction (AMI) has becoming a common leading cause of sudden death worldwide. MiR-96 has been identified that can target anti-apoptotic related genes in various human diseases. However, its role in AMI remains unclear. In this study, we found that miR-96 was significantly upregulated in the ischemic heart of MI mice (mice with myocardial infarction) and also in the H2O2-treated neonatal rat ventricular cardiomyocytes (CMs). In response H2O2, miR-96 inhibitor could significantly promote cell viability and reduce cell apoptosis of CMs, and inhibit the expression of Cleaved caspase-3 and Bax, while promote Bcl-2 expression. In addition, downregulation of miR-96 remarkedly reduced the infarct size and the percentages of apoptotic cells in the heart tissues of MI mice, and then protected against the damaged cardiac function. Moreover, we identified that XIAP (X-linked inhibitor of apoptosis) acted as a direct target gene of miR-96, meanwhile si-XIAP could obviously reverse miR-96 inhibitor induced protective effect in H2O2-treated CMs Taken together, our study demonstrated that miR-96 promoted AMI progression by directly targeting XIAP, and inhibiting the anti-apoptotic function of XIAP (Graphical abstract), which provided a novel therapeutic target for AMI treatment.

Gradient Mineralized and Porous Double-Network Hydrogel Effectively Induce the Differentiation of BMSCs into Osteochondral Tissue In Vitro for Potential Application in Cartilage Repair.

At present, it is a considerable challenge to mimic the complex architecture of osteochondral (OC) tissue. In this study, a porous and gradient mineralized double-network hydrogel is synthesized and used to induce bone marrow mesenchymal stem cells (BMSCs) to differentiate into the desired OC tissue depending only on the material and mechanical properties. Physical and chemical characterizations show that hydroxyapatite nanoparticles grow and fill into the pores of the hydrogel, and their content presents a gradient change in different layers of hydrogel. The synthesized hydrogel has excellent mechanical properties and the compression strength with different mineralization degrees varies from 27 to 380 kPa, which fully meets the needs of increased mechanical strength of articular cartilage from the surface to the deep layer. Besides, the synthesized hydrogel has good biocompatibility that can promote the proliferation and growth of BMSCs. More importantly, the results of histochemistry, immunohistochemistry, and real time polymerase chain reaction show that gradient mineralized hydrogel can induce BMSCs to differentiate into the desired chondrocytes and osteoblasts in different layers of hydrogels, indicating that OC tissues can be successfully constructed through a simple induction differentiation of gradient mineralized hydrogel.

Au@polydopamine nanoparticles/tocilizumab composite as efficient scavengers of oxygen free radicals for improving the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is the most common chronic autoimmune disorder associated with high-cost, side effects, and low therapeutic effects. To improve the treatment of RA, we originally developed a novel anti-RA Au@polydopamine nanoparticles (PDANPs)/TCZ composite using PDANPs as the binding sites of gold nanoparticles (AuNPs) and the drug carries of tocilizumab (TCZ) through a facile and environmentally-friend method, aiming to effectively scavenge oxygen free radicals (OFR) and inhibit the formation of related inflammatory factors. Characterizations showed that AuNPs with the size of 11.4 ± 2.9 nm randomly distributed onto the surface of PDANPs (145.8 ± 31.9 nm), meanwhile TCZ was chemically cross-linked to PDANPs through Schiff base linkage. The synthesized composite had good biocompatibility that can promote the proliferation and growth of chondrocytes and fibroblasts. More importantly, Au@PDANPs/TCZ composite showed more excellent abilities to scavenge OFR and inhibit the related inflammatory factors in vitro and in vivo than that of AuNPs and PDANPs owing to the synergistic scavenging effect, ensuring its best therapeutic effect in RA therapy. This new composite will have application potential in the treatment of RA related disease.

An anti-inflammatory isoflavone from soybean inoculated with a marine fungus Aspergillus terreus C23-3.

A new isoflavone derivative compound 1 (psoralenone) was isolated from soybean inoculated with a marine fungus Aspergillus terreus C23-3, together with seven known compounds including isoflavones 2-6, butyrolactone I (7) and blumenol A (8). Their structures were elucidated by MS, NMR, and ECD. Psoralenone displayed moderate in vitro anti-inflammatory activity in the LPS-induced RAW264.7 cell model. Compound 2 (genistein) showed moderate acetylcholinesterase (AChE) inhibitory activity whereas compounds 2, 5 (biochanin A), 6 (psoralenol), and 7 exhibited potent larvicidal activity against brine shrimp. Compounds 3 (daidzein), 4 (4'-hydroxy-6,7-dimethoxyisoflavone), and 5-7 showed broad-spectrum anti-microbial activity, and compound 7 also showed moderate 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity.