Homochiral Tetraphenylethene-Based Metal-Organic Frameworks with Circularly Polarized Luminescence for Enantioselective Recognition.

A pair of water-stable and highly porous homochiral fluorescent silver-organic framework enantiomers, namely, R-Ag-BPA-TPyPE (R-1) and S-Ag-BPA-TPyPE (S-1), had been prepared as enantioselective fluorescence sensors. Combining homochiral 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (BPA) with an AIE-based ligand tetrakis[4-(pyridin-4-yl)phenyl]ethene (TPyPE) in complexes R-1 and S-1 made them possess favorable circularly polarized luminescence (CPL) properties, and their CPL spectra were almost mirror images of each other. The luminescence dissymmetry factors (glum) are ±2.2 × 10-3 for R-1 and S-1, and the absolute fluorescence quantum yields (ΦFs) are 32.0% for R-1 and S-1, respectively. Complex R-1 could enantioselectively recognize two enantiomers of amino acids in water or DMF with high Stern-Volmer constants of 236-573 M-1 and enantioselectivity ratios of 1.40-1.78.

[A Growth Prediction Model of Pulmonary Ground-Glass Nodules Based on Clinical Visualization Parameters].

Objective To establish a model for predicting the growth of pulmonary ground-glass nodules (GGN) based on the clinical visualization parameters extracted by the 3D reconstruction technique and to verify the prediction performance of the model. Methods A retrospective analysis was carried out for 354 cases of pulmonary GGN followed up regularly in the outpatient of pulmonary nodules in Zhoushan Hospital of Zhejiang Province from March 2015 to December 2022.The semi-automatic segmentation method of 3D Slicer was employed to extract the quantitative imaging features of nodules.According to the follow-up results,the nodules were classified into a resting group and a growing group.Furthermore,the nodules were classified into a training set and a test set by the simple random method at a ratio of 7∶3.Clinical and imaging parameters were used to establish a prediction model,and the prediction performance of the model was tested on the validation set. Results A total of 119 males and 235 females were included,with a median age of 55.0 (47.0,63.0) years and the mean follow-up of (48.4±16.3) months.There were 247 cases in the training set and 107 cases in the test set.The binary Logistic regression analysis showed that age (95%CI=1.010-1.092,P=0.015) and mass (95%CI=1.002-1.067,P=0.035) were independent predictors of nodular growth.The mass (M) of nodules was calculated according to the formula M=V×(CTmean+1000)×0.001 (where V is the volume,V=3/4πR3,R:radius).Therefore,the logit prediction model was established as ln[P/(1-P)]=-1.300+0.043×age+0.257×two-dimensional diameter+0.007×CTmean.The Hosmer-Lemeshow goodness of fit test was performed to test the fitting degree of the model for the measured data in the validation set (χ2=4.515,P=0.808).The check plot was established for the prediction model,which showed the area under receiver-operating characteristic curve being 0.702. Conclusions The results of this study indicate that patient age and nodule mass are independent risk factors for promoting the growth of pulmonary GGN.A model for predicting the growth possibility of GGN is established and evaluated,which provides a basis for the formulation of GGN management strategies.

Research Progress on Exosomes and MicroRNAs in the Microenvironment of Postoperative Neurocognitive Disorders.

Postoperative neurocognitive disorder (PND) is a disease that frequently develops in older patients during the perioperative period. It seriously affects the quality of life of the affected patients. Despite advancements in understanding PND, this disorder's mechanisms remain unclear, including pathophysiological processes such as central synaptic plasticity and function, neuroinflammation, excitotoxicity, and neurotrophic support. Growing evidence suggests that microenvironmental changes are major factors for PND induction in older individuals. Exosomes are carriers for transporting different bioactive molecules between nerve cells in the microenvironment and maintaining intercellular communication and tissue homeostasis. Studies have shown that exosomes and microRNAs (miRNAs) are involved in various physiological and pathological processes, including neural processes related to PND, such as neurogenesis and cell death, neuroprotection, and neurotrophy. This article reviews the effects of exosomes and miRNAs on the brain microenvironment in PND and has important implications to improve PND diagnosis, as well as to develop targeted therapy of this disorder.

Accelerating Global Deletion of the Abnormal Toxicity Test for vaccines and biologicals. Planning common next steps. A workshop Report.

This online workshop Accelerating Global Deletion of the Abnormal Toxicity Test for vaccines and biologicals. Planning common next steps was organized on October 14th, 2021, by the Animal Free Safety Assessment Collaboration (AFSA), the Humane Society International (HSI), the European Federation of Pharmaceutical Industries and Associations (EFPIA), in collaboration with the International Alliance of Biological Standardization (IABS). The workshop saw a participation of over a hundred representatives from international organizations, pharmaceutical industries and associations, and regulatory authorities of 28 countries. Participants reported on country- and region-specific regulatory requirements and, where present, on the perspectives on the waiving and elimination of the Abnormal Toxicity Test. With AFSA, HSI, EFPIA and IABS representatives as facilitators, the participants also discussed specific country/global actions to further secure the deletion of ATT from all regulatory requirements worldwide.

[Application of multivariate models in whole process control of solid preparations].

The production of solid preparations is a multi-unit and multi-step system and is a whole process chain. Its quality is affected by many factors such as material properties and process parameters. As an important analysis tool, multivariate models play an important role in pharmaceutical monitoring. Besides, multivariate models can comprehensively understand the multi-factor relationship between material properties, process parameters, and quality attributes of products, thereby promoting the whole process optimization and controlling the drug production quality. This paper summarized the application of commonly used multivariate models in the process of solid preparations, which provides a certain reference for the process modeling of Chinese medicinal preparations.

Transplantation of mesenchymal stem cells for spinal cord injury: a systematic review and network meta-analysis.

Spinal cord injury (SCI) is a severe traumatic disease of the central nervous system, with a global prevalence of 236-4187 per million people. This meta-analysis aimed to evaluate the safety and efficacy of mesenchymal stem cells (MSCs) in treating patients with SCI as well as the optimal source and transplantation method of MSCs. PubMed, OVID, Cochrane, Web of Science, and China Biomedical Database were searched up until April 01, 2021. The study was conducted for five endpoints: American Spinal Injury Association (ASIA) motor and sensory score, ASIA grade improvement, Barthel Index (BI), and adverse reactions. Standard meta-analysis and network meta-analysis were performed using Stata 14.0. Eighteen studies with a total of 949 patients, were included in the meta-analysis. Standard meta-analysis showed that MSCs significantly improved ASIA motor score (P < 0.001), sensory score (P < 0.001), ASIA grade (P < 0.001), and BI (P < 0.001) compared to rehabilitation. In addition, in the network meta-analysis, autologous MSCs significantly improved the ASIA motor [MD = 8.01, 95% CI (4.27, 11.76)], sensory score [MD = 17.98, 95% CI (10.04, 25.91)], and BI [MD = 7.69, 95% CI (2.10, 13.29)] compared to rehabilitation. Similarly, compared to rehabilitation, intrathecal injection (IT) of MSCs significantly improved the ASIA motor [MD = 7.97, 95% CI (4.40, 11.53)] and sensory score [MD = 19.60, 95% CI (9.74, 29.46)]. Compared to rehabilitation, however, only the IL of MSCs was associated with more adverse reactions [OR = 17.82, 95% CI (2.48, 128.22)]. According to the results of SUCRA, both autologous MSCs and IT transplantation approaches most improved the neurological function in SCI patients. Cell transplantation using MSCs is effective in patients with SCI and IT of autologous MSCs may be more beneficial.

Sensitivity, specificity and limitation of in vitro hippocampal slice and neuron-based assays for assessment of drug-induced seizure liability.

An effective in vitro screening assay to detect seizure liability in preclinical development can contribute to better lead molecule optimization prior to candidate selection, providing higher throughput and overcoming potential brain exposure limitations in animal studies. This study explored effects of 26 positive and 14 negative reference pharmacological agents acting through different mechanisms, including 18 reference agents acting on glutamate signaling pathways, in a brain slice assay (BSA) of adult rat to define the assay's sensitivity, specificity, and limitations. Evoked population spikes (PS) were recorded from CA1 pyramidal neurons of hippocampus (HPC) in the BSA. Endpoints for analysis were PS area and PS number. Most positive references (24/26) elicited a concentration-dependent increase in PS area and/or PS number. The negative references (14/14) had little effect on the PS. Moreover, we studied the effects of 15 reference agents testing positive in the BSA on spontaneous activity in E18 rat HPC neurons monitored with microelectrode arrays (MEA), and compared these effects to the BSA results. From these in vitro studies we conclude that the BSA provides 93% sensitivity and 100% specificity in prediction of drug-induced seizure liability, including detecting seizurogenicity by 3 groups of metabotropic glutamate receptor (mGluR) ligands. The MEA results seemed more variable, both quantitatively and directionally, particularly for endpoints capturing synchronized electrical activity. We discuss these results from the two models, comparing each with published results, and provide potential explanations for differences and future directions.

Significance of Patient Participation in Nursing Care.

Patient participation, an international requirement according to the World Health Organization and other international bodies, is a must in nursing care. It involves patient engagement in making their own treatment decisions, participating in the development and evaluation of services and taking part in policy development. Patient participation on the individual, organizational and policy development levels has been discussed. Facilitators of and barriers to active patient participation, as well as ways to enhance it, were also included in this review. Poor communication, a paternalistic approach, time constraints, lack of encouragement and lack of information-sharing are some of the challenges associated with poor patient participation in nursing care. Facilitators of patient participation include empowering patients, involving them in making decisions and policy making, understanding their perspective about their role in their care and empowerment through leadership. Patient participation in nursing care has numerous benefits including effective healthcare services, improved patient safety, enhanced quality of care, fewer medication errors, more medication adherence and assessment of the care services received.

Investigating the theragnostic potential of 131I-caerin peptide in thyroid cancer.

OBJECTIVE: Caerin is a new peptide with tumour toxicity and its uptake by tumour cells is independent of the sodium iodide symporter (NIS). Thyroid cancer is the most common cancers of endocrine malignancy. Radioiodine (131I)-refractory thyroid cancer is the most lethal subtype of the thyroid cancers and remains a clinical challenge. In the current study, we investigated the 131I radiolabeling efficiency of Caerin and the effects of Caerin, 131I-Caerin and free 131I on differentiated and undifferentiated human thyroid cancer cell lines (B-CPAP and CAL-62) in vitro. MATERIALS AND METHODS: Cell Counting Kit-8 was used to assess the cytotoxic effect of Caerin, 131I-Caerin and free 131I on B-CPAP and CAL-62 cells. Laser scanning confocal microscope was exploited to evaluate the uptake and internalization of Caerin by thyroid cancer cells. The Chloramine-T method was used to label the peptide with 131I. And the stability and water partition coefficient (Log P) of 131I-Caerin were studied. RESULTS: Our results demonstrated that Caerin and 131I-Caerin could be accumulated by B-CPAP and CAL-62 cells, resulting in killing of the thyroid cancer cells in vitro. The efficacy of 131I-Caerin is much higher than 131I, especially to undifferentiated CAL-62 cells. The results prove the feasibility of radioiodination of the 131I-Caerin via the Chloramine-T method. Moreover, the result indicate the hydrophobic 131I-Caerin was stable in 72 hours. CONCLUSION: Iodine-131-Caerin can inhibit the cell viability of thyroid cancer and hold certain promise as a theragnostic tool for human thyroid cancers.

Highly sensitive detection of cancer-related genes based on complete fluorescence restoration of a molecular beacon with a functional overhang.

The accurate detection of cancer-related genes is of great significance for early diagnosis and targeted therapy of cancer. In this contribution, an automatically cycling operation of a functional overhang-containing molecular beacon (OMB)-based sensing system was proposed to perform amplification detection of the p53 gene. Contrary to the common molecular beacon (MB), a target DNA is designated to hybridize with a label-free recognition probe (RP) with a hairpin structure rather than OMB. In the presence of a target DNA of interest, the locked primer in RP opens and triggers the subsequent amplification procedures. The newly-developed OMB is not only capable of accomplishing cyclical nucleic acid strand-displacement polymerization (CNDP) with the help of polymerase and nicking endonuclease, but is also cleaved by restriction endonucleases, removing the quencher away from the fluorophore. Thus, the target DNA at an extremely low concentration is expected to generate a considerable amount of double-stranded and cleaved OMBs, and the quenched fluorescence is completely restored, leading to a dramatic increase in fluorescence intensity. Utilizing this sensing platform, the target gene can be detected down to 8.2 pM in a homogeneous way, and a linear response range of 0.01 to 150 nM could be obtained. More strikingly, the mutant genes can be easily distinguished from the wild-type ones. The proof-of-concept demonstrations reported herein are expected to promote the development of DNA biosensing systems, showing great potential in basic research and clinical diagnosis.

Protrusion-localized STAT3 mRNA promotes metastasis of highly metastatic hepatocellular carcinoma cells in vitro.

AIM: Recent evidence shows that localization of mRNAs and their protein products at cellular protrusions plays a decisive function in the metastasis of cancer cells. The aim of this study was to identify the variety of proteins encoded by protrusion-localized mRNAs and their roles in the metastasis and invasion of liver cancer cells. METHODS: Highly metastatic hepatocellular carcinoma cell line HCCLM3 and non-metastatic hepatocellular carcinoma cell line SMMC-7721 were examined. Cell protrusions (Ps) were separated from cell bodies (CB) using a Boyden chamber assay; total mRNA population in CB and Ps fractions was analyzed using high-throughput direct RNA sequencing. The localization of STAT3 mRNA and protein at Ps was confirmed using RT-qPCR, RNA FISH, and immunofluorescence assays. Cell migration capacity and invasiveness of HCCLM3 cells were evaluated using MTT, wound healing migration and in vitro invasion assays. The interaction between Stat3 and growth factor receptors was explored with co-immunoprecipitation assays. RESULTS: In HCCLM3 cells, 793 mRNAs were identified as being localized in the Ps fraction according to a cut-off value (Ps/CB ratio) >1.6. The Ps-localized mRNAs could be divided into 4 functional groups, and were all closely related to the invasive and metastatic properties. STAT3 mRNA accumulated in the Ps of HCCLM3 cells compared with non-metastatic SMMC-7721 cells. Treatment of HCCLM3 cells with siRNAs against STAT3 mRNA drastically decreased the cell migration and invasion. Moreover, Ps-localized Stat3 was found to interact with pseudopod-enriched platelet-derived growth factor receptor tyrosine kinase (PDGFRTK) in a growth factor-dependent manner. CONCLUSION: This study reveals STAT3 mRNA localization at the Ps of metastatic hepatocellular carcinoma HCCLM3 cells by combining application of genome-wide and gene specific description and functional analysis.

Rapid Selection of Patients Suitable for Deep Inspiration Breath-Hold Using an Automatic Delineating System and RapidPlan Model in Left Breast Cancer Patients undergoing Adjuvant Radiotherapy with IMRT.

PURPOSE: This study aimed to determine whether radiotherapy plans created using an automatic delineating system and a RapidPlan (RP) module could rapidly and accurately predict heart doses and benefit from deep inspiratory breath-hold (DIBH)in left breast cancer patients. METHODS AND MATERIALS: One hundred thirty-six clinically approved free breathing (FB) plans for patients with left breast cancer were included, defined as manual delineation-manual plan (MD-MP). A total of 104/136 plans were selected for RP model training. A total of 32/136 patients were automatically delineated by software, after which the RP generated plans, defined as automatic delineation-RapidPlan (AD-RP). In addition, 40 patients who used DIBH were included to analyze differences in heart benefits from DIBH. RESULTS: Two RP models were established for post breast-conserving surgery (BCS) and post modified radical mastectomy (MRM). There were no significant differences in most of the dosimetric parameters between the MD-MP and AD-RP. The heart doses of the two plans were strongly correlated in patients after BCS (0.80 ≤ r ≤ 0.88, P < 0.05) and moderately correlated in patients after MRM (0.46 ≤ r ≤ 0.58, P < 0.05). The RP model predicted the mean heart dose (MHD) within ± 59.67 cGy and ± 63.32 cGy for patients who underwent the two surgeries described above. The heart benefits from DIBH were significantly greater in patients with FB-MHD ≥ 4 Gy than in those with FB-MHD < 4 Gy. CONCLUSIONS: The combined automatic delineation RP model allows for the rapid and accurate prediction of heart dose under FB in patients with left breast cancer. FB-MHD ≥ 4 Gy can be used as a dose threshold to select patients suitable for DIBH.

[Content detemination of total tannin in Smilax glabra with reddish brown and off-white colored cross section].

There are two types of decoction of Smilax glabra due to its reddish brown or off-white colored cross section. These two kinds of decoction were found that they have large difference in anti-inflammatory effects and chemical constituents in the preliminary experiments. Comparing and analyzing the content of total tannin in these two kinds of decoction of S. glabra from 28 areas by UV-Vis spectrophotometry were first used to provide some experimental and theoretical development and utilization of this medicinal resource and quality control. Also, the sample recovery test required in Chinese Pharmacopoeia was improved by adding tannic acid instead of gallic acid to samples.

Investigation on the potential adverse outcome pathway of the sensitive endpoint for nephrotoxicity induced by gardenia yellow based on an integrated strategy using bioinformatics analysis and in vitro testing validation.

To explore the potential the adverse outcome pathway of Gardenia Yellow (GY)-induced sensitive endpoint for nephrotoxicity, an integrated strategy was applied in the present study. Using bioinformatic analysis, based on the constructed Protein-protein interaction networks, Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis on the core target network were performed to illustrate the potential gene targets and signal pathways. Then, the most enriched pathway was validated with Cell counting kit-8 assays and Western blot analysis in embryonic kidney epithelial 293 cell models. According to the findings, GY may interact with 321 targets related to the endpoint. The five targets on the top ranking in the PPI network were STAT3, SRC, HRAS, AKT1, EP300. Among them, PI3K/Akt was the most enriched pathway. In vitro testing showed that GY exerted a proliferative effect on the cell variability in a dose-dependent manner. GY at concentration of 1000 µg/ml and stimulation for 30 min can significantly enhance the expression of phosphorylated Akt. Thus, after the quantitative weight of evidence evaluation, Akt phosphorylation induced PI3K/Akt activation was speculated as a molecular initiating event leading to a proliferative and inflammatory response in renal tubular epithelial cells.

3, 4-Benzopyrene (Bap) aggravated abdominal aortic aneurysm formation by targeting pyroptosis in smooth muscle cells through ET-1 mediated NLRP3-inflammasome activation.

According to epidemiological studies, smoking is one of the leading causes of the high incidence of abdominal aortic aneurysms (AAA).3,4-Benzopyrene (Bap) is a by-product of coal tar and tobacco combustion produced by the incomplete combustion of organic fuels. It is an essential component of both automobile exhaust and tobacco smoke, it is also an important member of the air pollutants. However, the exact mechanism by which Bap can worsen the condition of patients with AAA and increase the mortality of patients with AAA remains unknown. This research aims to investigate the role of Bap in inducing pyroptosis in AAA. In vitro experiments, we revealed that pyroptosis-Gasdermin D (GSDMD) increased when Bap was used. Additionally, the release of inflammatory factors, such as IL-1ß and IL-18 were also rising. An mRNA sequencing analysis revealed that macrophages expressed a high level of the endothelin gene when cells were stimulated by Bap. It seemed that smooth muscle cells pyroptosis was related to macrophages. Experiments revealed that endothelin could increase the calcium ion concentration in smooth muscle cells, resulting in a large amount of ROS and activation of NLRP3 inflammasomes. We discovered that treatment with endothelin receptor antagonist (ABT-546) in vivo and calcium ion chelator (BAPTA) in vitro decreased AAA diameter, downregulated NLRP3 inflammasomes and ROS, and significantly reduced the number of activated GSDMD. Inflammatory mediators were released at a lower level. These findings suggest that Bap-induced pyroptosis may be mediated by the ET-1-Ca2+-inflammasome pathway, providing a new way to reduce mortality in AAA patients.

[Outcomes of IVF-ET and percentage of morphologically normal sperm before and after swim-up treatment].

OBJECTIVE: To study the relationship between sperm morphology and the outcomes of in vitro fertilization-embryo transfer (IVF-ET) before and after swim-up treatment of sperm on the day of oocyte retrieval. METHODS: This study included 94 couples to be treated by IVF-ET for tubal factor infertility. Sperm samples were collected on the day of oocyte retrieval and sperm morphology evaluated according to the Kruger criteria before and after swim-up treatment. Based on the results of morphological evaluation, the sperm samples were divided into groups A1 (morphologically normal sperm > or = 10% after swim-up treatment), A2 (morphologically normal sperm < 10% after swim-up treatment), B1 (morphologically normal sperm > or = 10% before swim-up treatment) and B2 (morphologically normal sperm < 10% before swim-up treatment). The outcomes of IVF-ET treatment were compared between groups A1 and A2 as well as between B1 and B2. RESULTS: After swim-up treatment, the rates of fertilization, cleavage, good quality embryo, clinical pregnancy and embryo implantation of group A1 were (72.72 +/- 3.35)%, (95.64 +/- 2.04)%, (24.39 +/- 4.57)%, 50.00% and 23.87%, respectively, while those of group A2 were (70.27 +/- 8.82)%, (94.82 +/- 4.94)%, (13.45 +/- 7.39)%, 9.52% and 6.25%, respectively, the latter three indexes remarkably higher in A1 than in A2 (P < 0.05), but the differences in the former two not statistically significant (P > 0.05). Before swim-up treatment, the above five indexes were (72.90 +/- 4.23)%, (95.20 +/- 2.61)%, (23.35 +/- 5.19)%, 39.58% and 18.35% in group B1, as compared with (71.33 +/- 5.10)%, (95.71 +/- 2.88)%, (20.18 +/- 6.15)%, 41.86% and 21.28% in group B2, with no statistically significant differences between the two groups (P > 0.05). CONCLUSION: The percentage of morphologically normal sperm after swim-up treatment on the day of oocyte retrieval may be a valuable predictor of the outcomes of IVF-ET.

A biological luminescent metal-organic framework with high fluorescence quantum yield for the selective detection of amino acids and monosaccharides.

The biological luminescent metal-organic framework (bio-LMOF), (Me2NH2)2[Zn6O(Ade)4(TCPPE)2] (1) {H4TCPPE = tetrakis[4-(4-carboxyphenyl)phenyl]ethene, Ade = adenine} was successfully designed and synthesized under hydrothermal conditions, with two channels of different sizes. The absolute fluorescence quantum yields of complex 1 and activated 1 are up to 77.6% and 85.9%, respectively. Activated 1 exhibits outstanding water stability and excellent selective luminescence sensing for amino acids and monosaccharides. The fluorescence quenching efficiencies of activated 1 towards L-Nph and D-Nga are 86.35% and 91.60%, respectively. Besides, activated 1 also displays highly quenching responses to L-Nph and D-Nga at fairly low concentrations, and the limits of detection for L-Nph and D-Nga are estimated to be 0.149 ppm and 1.612 ppm, respectively. Meanwhile, in multiple cycling experiments, activated 1 still has excellent cycling stability. These phenomena indicate that activated 1 can be utilized as a fast responsive biological luminescent sensor, which is a rare example for bio-LMOFs.

LncRNA RUNX1-IT1 affects the differentiation of Th1 cells by regulating NrCAM transcription in Graves' disease.

Graves' disease (GD) is a kind of autoimmune diseases. The development of GD is closely related to the imbalance of Th1/Th2 generated by the differentiation of CD4+ T cells. This study was sought to clarify the role of lncRNA RUNX1-IT1 and explore the mechanism of its function. The expressions of RUNX1-IT1 and Neural cell adhesion molecule (NrCAM) in the peripheral blood of GD patients were detected by qRT-PCR and Western blot. We performed RNA pull down, RIP, and ChIP experiments to verify the correlation between p53 and RUNX1-IT1, p53 and NrCAM. The levels of Th1 cells differentiation markers were detected by Flow cytometry assay and ELISA. The expressions of lncRNA RUNX1-IT1 and NrCAM were most significantly up-regulated in CD4+ T cells of GD patients, and NrCAM expression was significantly positively correlated with RUNX1-IT1 expression. Furthermore, p53 was a potential transcription factor of NrCAM, which could interact with NrCAM. NrCAM level was up-regulated after the overexpression of p53 in CD4+ T cells, while knockdown of RUNX1-IT1 reversed this effect. Down-regulation of NrCAM and RUNX1-IT1 could decrease the mRNA and protein levels of transcriptional regulator T-bet and CXC chemokine ligand 10 (CXCL10) in CD4+ T cells. Our results suggested that RUNX1-IT1 regulated the expressions of the important Th1 factor T-bet, CXCL10, and interferon γ (IFN-γ) by regulating NrCAM transcription, thus participating in the occurrence and development of specific autoimmune disease GD.

Generation of vascularized brain organoids to study neurovascular interactions.

Brain organoids have been used to recapitulate the processes of brain development and related diseases. However, the lack of vasculatures, which regulate neurogenesis and brain disorders, limits the utility of brain organoids. In this study, we induced vessel and brain organoids, respectively, and then fused two types of organoids together to obtain vascularized brain organoids. The fused brain organoids were engrafted with robust vascular network-like structures and exhibited increased number of neural progenitors, in line with the possibility that vessels regulate neural development. Fusion organoids also contained functional blood-brain barrier-like structures, as well as microglial cells, a specific population of immune cells in the brain. The incorporated microglia responded actively to immune stimuli to the fused brain organoids and showed ability of engulfing synapses. Thus, the fusion organoids established in this study allow modeling interactions between the neuronal and non-neuronal components in vitro, particularly the vasculature and microglia niche.

Understanding how the organs form and how their cells behave is essential to finding the causes and treatment for developmental disorders, as well as understanding certain diseases. However, studying most organs in live animals or humans is technically difficult, expensive and invasive. To address this issue, scientists have developed models called 'organoids' that recapitulate the development of organs using stem cells in the lab. These models are easier to study and manipulate than the live organs. Brain organoids have been used to recapitulate brain formation as well as developmental, degenerative and psychiatric brain conditions such as microcephaly, autism and Alzheimer's disease. However, these brain organoids lack the vasculature (the network of blood vessels) that supplies a live brain with nutrients and regulates its development, and which has important roles in brain disorders. Partly due to this lack of blood vessels, brain organoids also do not develop a blood brain barrier, the structure that prevents certain contents of the blood, including pathogens, toxins and even certain drugs from entering the brain. These characteristics limit the utility of existing brain organoids. To overcome these limitations, Sun, Ju et al. developed brain organoids and blood vessel organoids independently, and then fused them together to obtain vascularized brain organoids. These fusion organoids developed a robust network of blood vessels that was well integrated with the brain cells, and produced more neural cell precursors than brain organoids that had not been fused. This result is consistent with the idea that blood vessels can regulate brain development. Analyzing the fusion organoids revealed that they contain structures similar to the blood-brain barrier, as well as microglial cells (immune cells specific to the brain). When exposed to lipopolysaccharide ­ a component of the cell wall of certain bacteria ­ these cells responded by initiating an immune response in the fusion organoids. Notably, the microglial cells were also able to engulf connections between brain cells, a process necessary for the brain to develop the correct structures and work normally. Sun, Ju et al. have developed a new organoid system that will be of broad interest to researchers studying interactions between the brain and the circulatory system. The development of brain-blood-barrier-like structures in the fusion organoids could also facilitate the development of drugs that can cross this barrier, making it easier to treat certain conditions that affect the brain. Refining this model to allow the fusion organoids to grow for longer times in the lab, and adding blood flow to the system will be the next steps to establish this system.

Shexiang Baoxin Pill attenuates myocardial ischemia/reperfusion injury by activating autophagy via modulating the ceRNA-Map3k8 pathway.

BACKGROUND: The pathogenesis of myocardial ischemia/reperfusion is complex, involving multiple regulatory genes and environmental factors, and requiring the simultaneous regulation of multiple targets. Meanwhile, Traditional Chinese Medicine (TCM) has certain advantages in the comprehensive treatment of multi-site, multi-target conditions and overall regulation of this condition. This study explores the effect of the well-known TCM, the Shexiang Baoxin Pill (SBP) on myocardial ischemia/reperfusion injury in mice. MATERIALS AND METHODS: In vivo, 20 mg/kg/day SBP was administered by gavage for 28 days. In vitro, cardiomyocytes were pretreated with 25 µg/ml SBP for 24 h. Evans blue/TTC double-staining was employed to determine the infarct size. Markers of myocardial injury were detected in the serum and cell supernatants. The changes of pyroptosis and autophagy proteins were detected by western blot. Immunofluorescence, immunohistochemistry and PCR were performed to further illustrate the results. RESULTS: SBP significantly reduced the myocardial infarct size, decreased the myocardial injury markers, inhibited cardiomyocyte pyroptosis and oxidative stress, and promoted autophagy in vivo. In vitro, SBP alleviated cardiomyocyte pyroptosis, inhibited oxidative stress, reduced IL-1ß and IL-18 secretion, and unblocked autophagy flux. Myocardial injury is mitigated by SBP via the rapid degradation of autophagosomes, and SBP promotes the accumulation of autophagosomes by downregulating mmu_circ_0005874, Map3k8 and upregulating mmu-miR-543-3p. CONCLUSION: We found for the first time that SBP can inhibit pyroptosis and oxidative stress, and protect from myocardial I/R injury. In addition, it inhibits pyroptosis and improves H/R injury by promoting autophagosome generation and accelerating autophagic flux. SBP interferes with autophagy through the interaction between mmu_circ_0005874/mmu-miR-543-3p/Map3k8.