Advances in the study of plant-derived extracellular vesicles in the skeletal muscle system.

Plant-derived extracellular vesicles (PDEV) constitute nanoscale entities comprising lipids, proteins, nucleic acids and various components enveloped by the lipid bilayers of plant cells. These vesicles play a crucial role in facilitating substance and information transfer not only between plant cells but also across different species. Owing to its safety, stability, and the abundance of raw materials, this substance has found extensive utilization in recent years within research endeavors aimed at treating various diseases. This article provides an overview of the pathways and biological characteristics of PDEV, along with the prevalent methods employed for its isolation, purification, and storage. Furthermore, we comprehensively outline the therapeutic implications of diverse sources of PDEV in musculoskeletal system disorders. Additionally, we explore the utilization of PDEV as platforms for engineering drug carriers, aiming to delve deeper into the significance and potential contributions of PDEV in the realm of the musculoskeletal system.

Bu zhong Yiqi Decoction ameliorates mild cognitive impairment by improving mitochondrial oxidative stress damage via the SIRT3/MnSOD/OGG1 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Bu-Zhong-Yi-Qi Decoction(BZYQD) is a traditional formula commonly used in China, known for its effects in tonifying Qi and raising Yang. It can relieve symptoms of cognitive impairment such as forgetfulness and lack of concentration caused by qi deficiency, which is common in aging and debilitating. However, much of the current research on BZYQD has been focused on its impact on the digestive system, leaving its molecular mechanisms in improving cognitive function largely unexplored. AIM OF THE STUDY: Cognitive decline in the aging central nervous system is intrinsically linked to oxidative damage. This study aims to investigate the therapeutic mechanism of BZYQD in treating mild cognitive impairment caused by qi deficiency, particularly through repair of mitochondrial oxidative damage. MATERIALS AND METHODS: A rat model of mild cognitive impairment (MCI) was established by administering reserpine subcutaneously for two weeks, followed by a two-week treatment with BZYQD/GBE. In vitro experiments were conducted to assess the effects of BZYQD on neuronal cells using a H2O2-induced oxidative damage model in PC12 cells. The open field test and the Morris water maze test evaluated the cognitive and learning memory abilities of the rats. HE staining and TEM were employed to observe morphological changes in the hippocampus and its mitochondria. Mitochondrial activity, ATP levels, and cellular viability were measured using assay kits. Protein expression in the SIRT3/MnSOD/OGG1 pathway was analyzed in tissues and cells through western blotting. Levels of 8-OH-dG in mitochondria extracted from tissues and cells were quantified using ELISA. Mitochondrial morphology in PC12 cells was visualized using Mito Red, and mitochondrial membrane potential was assessed using the JC-1 kit. RESULTS: BZYQD treatment significantly improved cognitive decline caused by reserpine in rats, as well as enhanced mitochondrial morphology and function in the hippocampus. Our findings indicate that BZYQD mitigates mtDNA oxidative damage in rats by modulating the SIRT3/MnSOD/OGG1 pathway. In PC12 cells, BZYQD reduced oxidative damage to mitochondria and mtDNA in H2O2-induced conditions and was associated with changes in the SIRT3/MnSOD/OGG1 pathway. CONCLUSION: BZYQD effectively counteracts reserpine-induced mild cognitive impairment and ameliorates mitochondrial oxidative stress damage through the SIRT3/MnSOD/OGG1 pathway.

Reversible Facet Reconstruction of CdSe/CdS Core/Shell Nanocrystals by Facet-Ligand Pairing.

Synthesis of colloidal semiconductor nanocrystals with defined facet structures is challenging, though such nanocrystals are essential for fully realizing their size-dependent optical and optoelectronic properties. Here, for the mostly developed colloidal wurtzite CdSe/CdS core/shell nanocrystals, facet reconstruction is investigated under typical synthetic conditions, excluding nucleation, growth, and interparticle ripening. Within the reaction time window, two reproducible sets of facets─each with a specific group of low-index facets─can be reversibly reconstructed by switching the ligand system, indicating thermodynamic stability of each set. With a unique <0001> axis, atomic structures of the low-index facets of wurtzite nanocrystals are diverse. Experimental and theoretical studies reveal that each facet in a given set is paired with a common ligand in the solution, namely, either fatty amine and/or cadmium alkanoate. The robust bonding modes of ligands are found to be strongly facet-dependent and often unconventional, instead of following Green's classification. Results suggest that facet-controlled nanocrystals can be synthesized by optimal facet-ligand pairing either in synthesis or after-synthesis reconstruction, implying semiconductor nanocrystal formation with size-dependent properties down to an atomic level.

Single-cell sequencing of ascites fluid illustrates heterogeneity and therapy-induced evolution during gastric cancer peritoneal metastasis.

Peritoneal metastasis is the leading cause of death for gastrointestinal cancers. The native and therapy-induced ascites ecosystems are not fully understood. Here, we characterize single-cell transcriptomes of 191,987 ascites cancer/immune cells from 35 patients with/without gastric cancer peritoneal metastasis (GCPM). During GCPM progression, an increase is seen of monocyte-like dendritic cells (DCs) that are pro-angiogenic with reduced antigen-presenting capacity and correlate with poor gastric cancer (GC) prognosis. We also describe the evolution of monocyte-like DCs and regulatory and proliferative T cells following therapy. Moreover, we track GC evolution, identifying high-plasticity GC clusters that exhibit a propensity to shift to a high-proliferative phenotype. Transitions occur via the recently described, autophagy-dependent plasticity program, paligenosis. Two autophagy-related genes (MARCKS and TXNIP) mark high-plasticity GC with poorer prognosis, and autophagy inhibitors induce apoptosis in patient-derived organoids. Our findings provide insights into the developmental trajectories of cancer/immune cells underlying GCPM progression and therapy resistance.

The Efficacy and Safety of Celecoxib in Addition to Standard Cancer Therapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The purpose of this meta-analysis was to evaluate the efficacy and safety of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, in addition to standard anticancer therapy. Randomized controlled trials (RCTs) that evaluated the efficacy and safety of celecoxib-combined cancer therapy were systematically searched in PubMed and Embase databases. The endpoints were overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), objective response rate (ORR), disease control rate (DCR), pathological complete response (pCR), and adverse events (AEs). The results of 30 RCTs containing 9655 patients showed limited benefits in celecoxib-combined cancer therapy. However, celecoxib-combined palliative therapy prolonged PFS in epidermal growth factor receptor (EGFR) wild-type patients (HR = 0.57, 95%CI = 0.35-0.94). Moreover, despite a slight increase in thrombocytopenia (RR = 1.35, 95%CI = 1.08-1.69), there was no increase in other toxicities. Celecoxib combined with adjuvant therapy indicated a better OS (HR = 0.850, 95%CI = 0.725-0.996). Furthermore, celecoxib plus neoadjuvant therapy improved the ORR in standard cancer therapy, especially neoadjuvant therapy (overall: RR = 1.13, 95%CI = 1.03-1.23; neoadjuvant therapy: RR = 1.25, 95%CI = 1.09-1.44), but not pCR. Our study indicated that adding celecoxib to palliative therapy prolongs the PFS of EGFR wild-type patients, with good safety profiles. Celecoxib combined with adjuvant therapy prolongs OS, and celecoxib plus neoadjuvant therapy improves the ORR. Thus, celecoxib-combined cancer therapy may be a promising therapy strategy.

Early detection of gastric cancer via high-resolution terahertz imaging system.

Terahertz (THz) wave has demonstrated a good prospect in recent years, but the resolution is still one of the problems that restrict the application of THz technology in medical imaging. Paraffin-embedded samples are mostly used in THz medical imaging studies, which are thicker and significantly different from the current gold standard slice pathological examination in sample preparation. In addition, THz absorption in different layers of normal and cancerous tissues also remains to be further explored. In this study, we constructed a high-resolution THz imaging system to scan non-tumorous adjacent tissue slices and gastric cancer (GC) tissue slices. In this system, a THz quantum cascade laser emitted a pulsed 3 THz signal and the transmitted THz wave was received by a THz detector implemented in a 65 nm CMOS process. The slice thickness was only 20 µm, which was close to that of the medical pathology examination. We successfully found THz transmittance differences between different layers of normal gastric tissues based on THz images, and the resolution could reach 60 µm for the first time. The results indicated that submucosa had a lower THz transmittance than that of mucosa and muscular layer in non-tumorous adjacent tissue. However, in GC tissue, THz transmittance of mucosa and submucosa was similar, caused by the decreased transmittance of mucosa, where the cancer occurs. Therefore, we suppose that the similar terahertz transmittance between gastric mucosa and submucosa may indicate the appearance of cancerization. The images obtained from our THz imaging system were clearer than those observed with naked eyes, and can be directly compared with microscopic images. This is the first application of THz imaging technology to identify non-tumorous adjacent tissue and GC tissue based on the difference in THz wave absorption between different layers in the tissue. Our present work not only demonstrated the potential of THz imaging to promote early diagnosis of GC, but also suggested a new direction for the identification of normal and cancerous tissues by analyzing differences in THz transmittance between different layers of tissue.

Yangyin Fuzheng Jiedu Prescription exerts anti-tumor immunity in hepatocellular carcinoma by alleviating exhausted T cells.

BACKGROUND: Yangyin Fuzheng Jiedu Prescription (YFJP), a formulated Chinese herbal medicine, has been used for several decades in the treatment of hepatocellular carcinoma (HCC). Previous studies have demonstrated its anti-tumor efficacy, but the mechanism of action remains uncharacterized. This study aims to evaluate the therapeutic effect of YFJP on H22 tumor-bearing mice. PURPOSE: This study aimed to evaluate the therapeutic effect of YFJP on H22 tumor-bearing mice. METHODS: A total of 50 male H22 tumor-bearing mice were randomly divided into 6 groups and continuous administered either different doses of YFJP or cyclophosphamide (CTX) or normal saline. for 2 weeks. The tumor appearance was observed by taking photos, and the tumor volume, weight, spleen and thymus index were calculated. Morphology of tumor infiltrating lymphocytes and the CD8+ T lymphocytes were detected through HE staining immunohistochemistry respectively. The frequency of CD3+, CD8+ T cell subsets and co-inhibitory receptors PD-1, TIGIT, Tim-3 on CD8+ T cell in spleen, peripheral blood and tumor tissue was performed by flow cytometry. Meanwhile, the killing and apoptotic functions of CD8+ T cells in tumor tissues were also detected by the same method. The levels of cytokines in peripheral blood were detected by Milliplex map mouse highs sensitivity T Cell kit. The expression of T cell transcription factor T-bet and Eomes in tumor tissues were observed by Western blot. RESULTS: We found that YFJP could effectively inhibit the solid tumor growth and spleen indexes, but showed little effect on the body weight in the established mouse model of HCC. Furthermore, we investigated the effect of YFJP on the phenotypic and functional changes of T cells. The results showed that YFJP could maintain the high ratio of CD3+ and CD8+ T cells in the peripheral blood, spleen, and tumor tissues while decreasing the expression of programmed cell death-1 (PD-1), T cell immunoglobulin and ITIM domain (TIGIT), T cell immunoglobulin domain and mucin domain-3 (Tim-3) in CD8+ T cells, respectively. Surprisingly, PD-1/Tim-3 double-positive T cells in the peripheral blood and tumor tissues were significantly decreased. Additionally, YFJP restored the cytotoxicity of tumor-infiltrating T cells and delayed their apoptosis in H22 tumor-bearing mice. In addition, treatment with YFJP significantly decreased the expression of inflammatory and immunosuppressive cytokines (including IL-1ß, IL-6, and IL-10) in the serum and tumor tissues whereas enhancing that of effector cytokines TNF-α, and IFN-γ. Moreover, T cell transcription factors T-bet increased and Eomes degraded in the tumor tissues upon YFJP treatment. CONCLUSION: In conclusion, these results demonstrated that YFJP could simultaneously exert anti-tumor immune response in H22 tumor-bearing mice by alleviating T cell exhaustion and immunosuppression.

The RIG-I Signal Pathway Mediated Panax notoginseng Saponin Anti-Inflammatory Effect in Ischemia Stroke.

Panax notoginseng saponins (PNS), the main bioactive constituents of a traditional Chinese herb Panax notoginseng, were commonly used for ischemic stroke in China. However, the associated cellular and molecular mechanisms of PNS have not been well examined. This study aimed to decipher the underlying molecular target of PNS in the treatment of cerebral ischemia. The oxygen-glucose-deprived (OGD) model of rat brain microvascular endothelial cells (BMECs) was used in this study. The alteration of gene expression in rat BMECs after PNS treatment was measured by microarray and indicated that there were 38 signaling pathways regulated by PNS. Among them, RIG-I receptor and related signaling molecules TNF receptor-associated factor 2 (Traf2) and nuclear factor-kappa B (NF-κB) were significantly suppressed by PNS, which was verified again in OGD-induced BMECs measured by FQ-PCR and western blotting and in middle cerebral artery occlusion (MCAO) rats measured by immunohistochemistry. The levels of TNF-α, IL-8, and the downstream cytokines regulated by RIG-I receptor pathway were also decreased by PNS. Meanwhile, the neurological evaluation, hematoxylin and eosin (HE) staining, and Evans blue staining were conducted to evaluate the effect of PNS in MCAO rats. Results showed PNS significantly improved functional outcome and cerebral vascular leakage. Flow cytometry showed the number of the inflammatory cells infiltrated in brain tissue was decreased in PNS treatment. Our results identified that RIG-I signaling pathway mediated anti-inflammatory properties of PNS in cerebral ischemia, which provided the novel insights of PNS application in clinics.

GAT-LI: a graph attention network based learning and interpreting method for functional brain network classification.

BACKGROUND: Autism spectrum disorders (ASD) imply a spectrum of symptoms rather than a single phenotype. ASD could affect brain connectivity at different degree based on the severity of the symptom. Given their excellent learning capability, graph neural networks (GNN) methods have recently been used to uncover functional connectivity patterns and biological mechanisms in neuropsychiatric disorders, such as ASD. However, there remain challenges to develop an accurate GNN learning model and understand how specific decisions of these graph models are made in brain network analysis. RESULTS: In this paper, we propose a graph attention network based learning and interpreting method, namely GAT-LI, which learns to classify functional brain networks of ASD individuals versus healthy controls (HC), and interprets the learned graph model with feature importance. Specifically, GAT-LI includes a graph learning stage and an interpreting stage. First, in the graph learning stage, a new graph attention network model, namely GAT2, uses graph attention layers to learn the node representation, and a novel attention pooling layer to obtain the graph representation for functional brain network classification. We experimentally compared GAT2 model's performance on the ABIDE I database from 1035 subjects against the classification performances of other well-known models, and the results showed that the GAT2 model achieved the best classification performance. We experimentally compared the influence of different construction methods of brain networks in GAT2 model. We also used a larger synthetic graph dataset with 4000 samples to validate the utility and power of GAT2 model. Second, in the interpreting stage, we used GNNExplainer to interpret learned GAT2 model with feature importance. We experimentally compared GNNExplainer with two well-known interpretation methods including Saliency Map and DeepLIFT to interpret the learned model, and the results showed GNNExplainer achieved the best interpretation performance. We further used the interpretation method to identify the features that contributed most in classifying ASD versus HC. CONCLUSION: We propose a two-stage learning and interpreting method GAT-LI to classify functional brain networks and interpret the feature importance in the graph model. The method should also be useful in the classification and interpretation tasks for graph data from other biomedical scenarios.

Interpretable Learning Approaches in Resting-State Functional Connectivity Analysis: The Case of Autism Spectrum Disorder.

Deep neural networks have recently been applied to the study of brain disorders such as autism spectrum disorder (ASD) with great success. However, the internal logics of these networks are difficult to interpret, especially with regard to how specific network architecture decisions are made. In this paper, we study an interpretable neural network model as a method to identify ASD participants from functional magnetic resonance imaging (fMRI) data and interpret results of the model in a precise and consistent manner. First, we propose an interpretable fully connected neural network (FCNN) to classify two groups, ASD versus healthy controls (HC), based on input data from resting-state functional connectivity (rsFC) between regions of interests (ROIs). The proposed FCNN model is a piecewise linear neural network (PLNN) which uses piecewise linear function LeakyReLU as its activation function. We experimentally compared the FCNN model against widely used classification models including support vector machine (SVM), random forest, and two new classes of deep neural network models in a large dataset containing 871 subjects from ABIDE I database. The results show the proposed FCNN model achieves the highest classification accuracy. Second, we further propose an interpreting method which could explain the trained model precisely with a precise linear formula for each input sample and decision features which contributed most to the classification of ASD versus HC participants in the model. We also discuss the implications of our proposed approach for fMRI data classification and interpretation.

Development of an infrared polarized microscope for evaluation of high gradient stress with a small distribution area on a silicon chip.

In this paper, a special microscope to evaluate stress in a silicon chip was developed based on the principle of photoelasticity. To facilitate stress measurements and to improve their precision, two methods were adopted. First, a six-step phase shifting technique was realized with the aid of two motorized rotation stages. During the implementation of this phase shifting technique, six digital images were captured at different rotation angles of the two stages and employed to automatically calculate the birefringence. Second, an algorithm was developed to correct deviations in the position of the specimen in the six images caused by mechanical vibration; thus, the most significant source of error was addressed. The precision of the system in terms of measuring the stress-birefringence phase difference was verified with a standard quarter wave plate; the results demonstrate that the system is precise to within at least 2°. With the developed system, we evaluated the stress distribution and its variations with thermal cycling around through-silicon vias on a silicon chip at room temperature; we found that stress initially increased with the number of thermal cycles before decreasing with further thermal cycles.

[Comparison of the curative effect between over-elbow splint and traditional small splint fixation in the treatment of comminuted Colles fracture].

OBJECTIVE: To analyze the clinical efficacy of over-elbow small splint fixation for the treatment of comminuted Colles fractures. METHODS: From October 2013 to October 2015, 52 patients with comminuted Colles fracture were divided into two groups (the traditional splint fixation group and the over-elbow small splint fixation group) according to the treatment strategy. There were 26 patients in the over-elbow small splint fixation group including 7 males and 19 females with an average age of (64.615±11.475) years old ranging from 38 to 85 years old, and 26 patients in the traditional splint fixation group including 9 males and 17 females with an average age of (65.269±13.162) years old ranging 36 to 91 years old, respectively. In the over-elbow small splint fixation group, 3 cases were type A3 fractures, 9 cases were type C1, 7 cases were type C2 and 7 cases were type C3;in the traditional splint fixation group, 4 cases were type A3, 8 cases were type C1, 9 cases were type C2 and 5 cases were type C3. After manipulative reduction, the fractures in traditional splint fixation group were fixed with traditional small splint, and the fractures in over-elbow small splint fixation group were added with over-elbow right angle splint for the first three weeks, then continued fixing like the control group until clinical cicatrization. All patients in both groups were regularly taken X-ray examination and changed dressings to obtain the clinical healing. Patients were guided to do functional exercise after splints were taken off. The therapeutic effects were evaluated according to modified Green and O'Brein score system after 8 weeks' functional exercise. RESULTS: All patients got clinical healing without severe complications in both groups. The shortened length of radius in traditional splint fixation group was more than that in over-elbow small splint fixation group (5.923±1.978) mm VS (2.962±1.248) mm(P<0.05). There was no significant difference in radial incline between two groups. There was a higher wrist score in over-elbow small splint fixation group compared with traditional splint fixation group 89.615±11.482 vs 80.385±13.485(P<0.05). CONCLUSIONS: Over-elbow small splint fixation is better than traditional splint fixation for the treatment of comminuted Colles fracture because of reliable clinical result and excellent wrist functional recovery.

Photoredox-Induced Functionalization of Alkenes for the Synthesis of Substituted Imidazolines and Oxazolidines.

A one-pot, three-component cascade reaction combining photoredox catalyzed radical addition and formal [3 + 2] annulation was developed. With this approach, highly concise syntheses of imidazoline and oxazolidine derivatives have been achieved. The advantages of this transformation are good to excellent yields, mild reaction conditions, operational simplicity, and easy accessibility of raw materials.

[Case-control study on small splint fixation with trapezoid pad and plaster slab fixation for the treatment of comminuted Colles fracture].

OBJECTIVE: To compare the clinical efficacy of trapezoid pad coordinate with small splint fixation treatment with plaster slab fixation treatment for comminuted Colles fracture. METHODS: From October 2010 to March 2012,80 outpatients with comminuted Colles fracture were divided into two groups. There were 40 patients in trapezoid pad splint fixation treatment group and 40 patients in pipe type plaster control group. There were 13 males and 27 females in trapezoid pad splint fixation treatment group,with an average age of (62.1 +/- 19.2) years old. And there were 15 males and 25 females in pipe type plaster control group,with an average age of (60.2 +/- 19.5) years old. After treated with manipulative reduction,the fractures were fixed with pipe plaster in the control group, and were fixed with trapezoid pad joint by small splint in the treatment group. The patients in both groups were regularly taken X-ray recheck and changed dressings to obtain the clinical healing. Patients were guided to do functional exercise after splints were taken off. The therapeutic effects were evaluated according to Gartland-Werlley wrist score when splints taken off and after 2 months. RESULTS: According to wrist score, the average scores in the treatment group were (8.1 +/- 2.8) when splints taken off and (5.3 +/- 4.5) after 2 months. And the average scores in the control group were (10.3 +/- 2.6) when splints taken off and (8.4 +/- 5.8) after 2 months. The score in the treatment group was higher than that of control group. The average shortened lengths of radius were (4.8 + 1.7) mm in the treatment group and (8.2 +/- 2.1) mm in the control group. The shortened length of control group was larger than that of treatment group. CONCLUSION: Trapezoid pad coordinated with small splint fixation is better than traditional pipe type plaster for treating comminuted Colles fracture.

[To compare and research the clinical effect of treating the comminute distal radius fractures by refining splintage].

OBJECTIVE: To treat the comminute distal radius fractures by improved splint, and obersve the curative effect and compare the radiology with the traditional splint. METHODS: Ninety-two patients with distal radius comminute fracture were randomly divided into two groups. There were 38 males and 54 females. The average age was 63 years old ranging from 23 to 82. Acording to AO classification on the distal fracture of the radius, there were 15 cases of A3, 40 cases of C1, 26 cases of C2 and 11 cases of C3. After all patients were treated by manipulative reduction, 46 cases of the treatment group were fixed supra-carpometacarpal joints by improved splint and trapezoid pad, the other 46 cases of control group were treated with the traditional spilint. Both groups were regularly taken X-ray recheck and changed dressings to obtain the clinical cicatrization. Patients were guided to do functional exercise after splints were taken off. Six weeks later all patients were evaluated the curative and radiologic effect according to Gartland-Werlley wrist score and Lidstrom grade respectively. RESULTS: According to wrist score,there were 13 cases on excellent, 34 cases on fine and 9 cases on normal in treatment group, which average score was (4.0 +/- 2.6) and the percent of wrist functional fitness was 80.6%. There were 9 cases on excellen, 19 cases on fine and 18 cases on normal in control group, which average score was (6.0 +/- 4.2) and the percent of wrist grad and 4 cases on the third grade in treatment group. There were 22 cases on the first grade, 16 cases on the second grad and 8 cases on the third grade in control group. CONCLUSION: The outcome of improved splint was better than that of traditional splint on the function and radiology for treating the comminute distal radius fracture.