Pharmacodynamics and mechanism of Erigeron breviscapus granules in the treatment of ischemic stroke in mice by regulating sphingolipid metabolism based on metabolomics.

AIM: Erigeron breviscapus (Vant.) Hand.-Mazz. (EB) granules is the extract preparation of EB, with clear curative effect and unclear mechanism. This study intends to systematically explore the specific mechanism of EB granules in the treatment of IS from the metabolic perspective. METHODS: The model of transient middle cerebral artery occlusion (tMCAO) in mice was established by the suture-occluded method. The therapeutic effect of EB granules on tMCAO mice was evaluated by behavioral evaluation, brain water content determination, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (HE) staining, and levels of lactate dehydrogenase (LDH) and neuron specific enolase (NSE) in serum. In order to screen differential metabolites, non-targeted metabolomics technology was used to detect the metabolites in serum before and after administration. Univariate statistics, multivariate statistics and bioinformatics were used to analyze the changes of metabolites in serum of tMCAO mice. The possible related mechanism of EB granules in treating IS was screened by pathway enrichment analysis, and the preliminary verification was carried out at animal level by enzyme linked immunosorbent assay (ELISA) and western blot (WB). RESULTS: EB granules could significantly improve behavior of tMCAO mice, reduce brain water content and cerebral infarction volume, improve morphology of brain tissue, reduce the levels of LDH and NSE in serum. A total of 232 differential metabolites were screened, which were mainly enriched in many biological processes such as sphingolipid metabolism. The differential metabolite S1P and its receptors S1PR1 and S1PR2 in sphingolipid metabolism were verified. The results showed that the level of S1P in brain tissue increased and the protein expression of S1PR1 decreased significantly after modeling, and reversed after administration, but there was no significant difference in the protein expression of S1PR2. CONCLUSION: The therapeutic effects of EB granules may be related to affecting sphingolipid metabolism through regulating S1P/S1PR1.

Structures and organizations of PSI-AcpPCI supercomplexes from red tidal and coral symbiotic photosynthetic dinoflagellates.

Marine photosynthetic dinoflagellates are a group of successful phytoplankton that can form red tides in the ocean and also symbiosis with corals. These features are closely related to the photosynthetic properties of dinoflagellates. We report here three structures of photosystem I (PSI)-chlorophylls (Chls) a/c-peridinin protein complex (PSI-AcpPCI) from two species of dinoflagellates by single-particle cryoelectron microscopy. The crucial PsaA/B subunits of a red tidal dinoflagellate Amphidinium carterae are remarkably smaller and hence losing over 20 pigment-binding sites, whereas its PsaD/F/I/J/L/M/R subunits are larger and coordinate some additional pigment sites compared to other eukaryotic photosynthetic organisms, which may compensate for the smaller PsaA/B subunits. Similar modifications are observed in a coral symbiotic dinoflagellate Symbiodinium species, where two additional core proteins and fewer AcpPCIs are identified in the PSI-AcpPCI supercomplex. The antenna proteins AcpPCIs in dinoflagellates developed some loops and pigment sites as a result to accommodate the changed PSI core, therefore the structures of PSI-AcpPCI supercomplex of dinoflagellates reveal an unusual protein assembly pattern. A huge pigment network comprising Chls a and c and various carotenoids is revealed from the structural analysis, which provides the basis for our deeper understanding of the energy transfer and dissipation within the PSI-AcpPCI supercomplex, as well as the evolution of photosynthetic organisms.

ENPP2 inhibitor improves proliferation in AOM/DSS-induced colorectal cancer mice via remodeling the gut barrier function and gut microbiota composition.

In our previous multicenter study, we delineated the inherent metabolic features of colorectal cancer (CRC). Therein, we identified a member of the ectonucleotide pyrophosphatase/ phosphodiesterase family (ENPP2) as a significant differential metabolite of CRC. In this study, the role of ENPP2 in CRC has been demonstrated using established in vitro and in vivo models including ENPP2 gene knockdown, and use of the ENPP2 inhibitor, GLPG1690. We found that CRC proliferation was decreased after either ENPP2 gene knockdown or use of ENPP2 inhibitors. We further evaluated the role of GLPG1690 in AOM/DSS-induced CRC mice via intestinal barrier function, macrophage polarization, inflammatory response and microbial homeostasis. Results of immunofluorescence staining and Western blotting showed that GLPG1690 can restore gut-barrier function by increasing the expression of tight junction proteins, claudin-1, occludin and ZO-1. M2 tumor-associated macrophage polarization and colonic inflammation were attenuated after treatment with GLPG1690 using the Azoxymethane/Dextran Sodium Sulfate (AOM/DSS) model. Moreover, 16 S rDNA pyrosequencing and metagenomic analysis showed that GLPG1690 could alleviate gut dysbiosis in mice. Furthermore, administration of GLPG1690 with antibiotics as well as fecal microbiota transplantation assays demonstrated a close link between the efficacy of GLPG1690 and the gut microbiota composition. Finally, results of metabolomic analysis implicated mainly the gut microbiota-derived metabolites of aromatic amino acids in CRC progression. These findings may provide novel insights into the development of small-molecule ENPP2 inhibitors for the treatment of CRC.

Saponin of Aralia taibaiensis promotes angiogenesis through VEGF/VEGFR2 signaling pathway in cerebral ischemic mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Aralia taibaiensis is known for its ability to promote blood circulation and dispel blood stasis, activate meridians and remove arthralgia. The saponins of Aralia taibaiensis (sAT) are the main active components that are often used to treat cardiovascular and cerebrovascular diseases. However, it has not been reported whether sAT can improve ischemic stroke (IS) by promoting angiogenesis. AIM OF THE STUDY: In this study, we investigated the potential of sAT to promote post-ischemic angiogenesis in mice and determined the underlying mechanism through in vitro experiments. METHODS: To establish the middle cerebral artery occlusion (MCAO) mice model in vivo. First of all, we examined the neurological function, brain infarct volume, and degree of brain swelling in MCAO mice. We also observed pathological changes in brain tissue, ultrastructural changes in blood vessels and neurons, and the degree of vascular neovascularization. Additionally, we established the oxygen-glucose deprivation/reoxygenation (OGD/R) -human umbilical vein endothelial cells (HUVECs) model in vitro to detect the survival, proliferation, migration and tube formation of OGD/R HUVECs. Finally, we verified the regulatory mechanism of Src and PLCγ1 siRNA on sAT promoting angiogenesis by cell transfection technique. RESULTS: In the cerebral ischemia-reperfusion mice, sAT distinctly improved the cerebral infarct volume, brain swelling degree, neurological dysfunction, and brain histopathological morphology due to cerebral ischemia/reperfusion injury. It also increased the double positive expression of BrdU and CD31 in brain tissue, promoted the release of VEGF and NO and decreased the release of NSE and LDH. In the OGD/R HUVECs, sAT significantly improved cell survival, proliferation, migration and tube formation, promoted the release of VEGF and NO, and increased the expression of VEGF, VEGFR2, PLCγ1, ERK1/2, Src and eNOS. Surprisingly, the effect of sAT on angiogenesis was inhibited by Src siRNA and PLCγ1 siRNA in OGD/R HUVECs. CONCLUSION: The results proved that sAT promotes angiogenesis in cerebral ischemia-reperfusion mice and its mechanism is to regulate VEGF/VEGFR2 and then regulate Src/eNOS and PLCγ1/ERK1/2.

Is RDW a clinically relevant prognostic factor for newly diagnosed multiple myeloma? A systematic review and meta-analysis.

BACKGROUND: Multiple myeloma (MM) is an incurable plasma cell malignancy. Red cell distribution width (RDW) is a prognostic marker in various diseases, solid tumors, and hematologic neoplasms, but its prognostic significance in MM is controversial. In this study, we aimed to assess the relationship between RDW and the clinical prognosis of MM patients through a meta-analysis. METHODS: Relevant literature were retrieved from PubMed, Embase, and Web of Science databases according to PRISMA guideline. All relevant parameters were extracted and combined for statistical analysis. The effect size was presented as hazard ratio (HR)/odds ratio (OR) and 95% confidence interval (CI). HR/OR > 1 in MM patients with high RDW suggested a worse prognosis. Heterogeneity test evaluation was performed using Cochran's Q test and I2 statistics. A Pheterogeneity < 0.10 or I2 > 50% suggested significant heterogeneity. P < 0.05 was considered statistically significant. Statistical analysis was performed using Stata 12.0 software. RESULTS: 8 articles involving 9 studies with 1165 patients were included in our meta-analysis. Our results suggested that elevated RDW is significantly associated with poor prognosis in MM (OS: HR = 1.91, 95%CI: 1.48-2.46; PFS: HR = 2.87, 95% CI: 2.02-4.07). A significant correlation was not found between RDW and International Staging System (ISS) staging (ISS III VS ISS I-II: OR:1.53; 95%CI:0.97-2.42). CONCLUSION: Our results suggested that RDW is a robust predictor of newly diagnosed MM outcomes.

The Prognostic Significance of the BIN1 and CCND2 Gene in Adult Patients with Acute Myeloid Leukemia.

To investigate the expression and clinical significance of Bridging INtegrator 1 (BIN1) and cyclin D2 (CCND2) in newly diagnosed cytogenetically heterogenous adult acute myeloid leukemia patients. Methods Real-time quantitative PCR (RQ-PCR) was used to detect the expression of BIN1 and CCND2 genes in 49 newly diagnosed adult patients with AML, and their clinical significance was analyzed. Results BIN1 and CCND2 genes are highly expressed in patients with AML, which suggest their potential as molecular markers. A statistical significant correlation was found between BIN1 expression with bone marrow blasts (P = 0.012), CD34 expression (P = 0.026), NLR (P = 0.019) and Karyotype risk (P = 0.005). There was a statistically significant correlation between CCND2 and age (P = 0.001), NLR (P = 0.046) Karyotype risk (P = 0.033). The expression level of BIN1 was related to early treatment response (CR or not) (P = 0.043). CCND2 expression was significantly correlated with overall survival (P = 0.013), but not with CR (P = 0.731). Conclusion BIN1 and CCND2 genes are highly expressed in patients with AML, suggesting the potential of these two genes as molecular markers. Moreover, high levels of CCND2 are associated with better prognosis, suggesting the possibility of these two genes as prognostic markers.

Two-Stage Assembly of Nanoparticle Superlattices with Multiscale Organization.

Self-assembly processes, while promising for enabling the fabrication of complexly organized nanomaterials from nanoparticles, are often limited in creating structures with multiscale order. These limitations are due to difficulties in practically realizing the assembly processes required to achieve such complex organizations. For a long time, a hierarchical assembly attracted interest as a potentially powerful approach. However, due to the experimental limitations, intermediate-level structures are often heterogeneous in composition and structure, which significantly impacts the formation of large-scale organizations. Here, we introduce a two-stage assembly strategy: DNA origami frames scaffold a coordination of nanoparticles into designed 3D nanoclusters, and then these clusters are assembled into ordered lattices whose types are determined by the clusters' valence. Through modulating the nanocluster architectures and intercluster bindings, we demonstrate the successful formation of complexly organized nanoparticle crystals. The presented two-stage assembly method provides a powerful fabrication strategy for creating nanoparticle superlattices with prescribed unit cells.

Corrigendum to "Salvia miltiorrhiza and the Volatile of Dalbergia odorifera Attenuate Chronic Myocardial Ischemia Injury in a Pig Model: A Metabonomic Approach for the Mechanism Study".

[This corrects the article DOI: 10.1155/2021/8840896.].

Are the Derived Indexes of Peripheral Whole Blood Cell Counts (NLR, PLR, LMR/MLR) Clinically Significant Prognostic Biomarkers in Multiple Myeloma? A Systematic Review And Meta-Analysis.

BACKGROUND: Multiple myeloma (MM) is an incurable malignant plasma cell tumor. Whole blood cell count (WBCC) derived indexes are widely used as a predictive biomarker for various types of solid and hematological malignant tumors. Our study is to evaluate its effectiveness in MM by meta-analysis. METHODS: Relevant literatures were retrieved from PubMed, Embase and Web of Science databases according to PRISMA guideline. All relevant parameters were extracted and combined for statistical analysis. RESULTS: Nineteen studies incorporating 3818 MM patients were eventually included in this meta-analysis. 13 studies evaluated that elevated NLR was significantly associated with poor survival outcomes (OS: HR=2.04, P<0.001; PFS: HR=1.96, P=0.003). Elevated NLR was revealed to correlate with ISS stage (ISS III VS I-II, OR=2.23, P=0.003). A total of 7 studies have shown that elevated LMR predicts a better prognosis in MM patients (OS: HR=0.57, P<0.001; PFS: HR=0.49, P<0.05), and two other studies demonstrated that increased MLR was related to poor OS/PFS (OS: HR=1.58, P<0.05; PFS: HR=1.60, P<0.05). However, in the other 6 studies including 1560 patients, the prognostic value of PLR had not been confirmed (OS: HR=0.89, P>0.05; PFS: HR=0.87, P>0.05). CONCLUSIONS: The indexes NLR and LMR/MLR derived from WBCC were validated to be useful biomarkers to predict the prognosis in MM patients, but the evidence of PLR was insufficient.

Network pharmacology and molecular docking reveal the effective substances and active mechanisms of Dalbergia Odoriferain protecting against ischemic stroke.

Dalbergia Odorifera (DO) has been widely used for the treatment of cardiovascular and cerebrovascular diseasesinclinical. However, the effective substances and possible mechanisms of DO are still unclear. In this study, network pharmacology and molecular docking were used toelucidate the effective substances and active mechanisms of DO in treating ischemic stroke (IS). 544 DO-related targets from 29 bioactive components and 344 IS-related targets were collected, among them, 71 overlapping common targets were got. Enrichment analysis showed that 12 components were the possible bioactive components in DO, which regulating 9 important signaling pathways in 3 biological processes including 'oxidative stress' (KEGG:04151, KEGG:04068, KEGG:04915), 'inflammatory response'(KEGG:04668, KEGG:04064) and 'vascular endothelial function regulation'(KEGG:04066, KEGG:04370). Among these, 5 bioactive components with degree≥20 among the 12 potential bioactive components were selected to be docked with the top5 core targets using AutodockVina software. According to the results of molecular docking, the binding sites of core target protein AKT1 and MOL002974, MOL002975, and MOL002914 were 9, 8, and 6, respectively, and they contained 2, 1, and 0 threonine residues, respectively. And some binding sites were consistent, which may be the reason for the similarities and differences between the docking results of the 3 core bioactive components. The results of in vitro experiments showed that OGD/R could inhibit cell survival and AKT phosphorylation which were reversed by the 3 core bioactive components. Among them, MOL002974 (butein) had a slightly better effect. Therefore, the protective effect of MOL002974 (butein) against cerebral ischemia was further evaluated in a rat model of middle cerebral artery occlusion (MCAO) by detecting neurological score, cerebral infarction volume and lactate dehydrogenase (LDH) level. The results indicated that MOL002974 (butein) could significantly improve the neurological score of rats, decrease cerebral infarction volume, and inhibit the level of LDH in the cerebral tissue and serum in a dose-dependent manner. In conclusion, network pharmacology and molecular docking predicate the possible effective substances and mechanisms of DO in treating IS. And the results are verified by the in vitro and in vivo experiments. This research reveals the possible effective substances from DO and its active mechanisms for treating IS and provides a new direction for the secondary development of DO for treating IS.

Network pharmacology-based prediction of the active compounds and mechanism of Buyang Huanwu Decoction for ischemic stroke.

Buyang Huanwu Decoction (BYHWD) is used to promote blood circulation and is widely used in Chinese clinical practice for the treatment and prevention of ischemic cerebral vascular diseases. However, the mechanism and active compounds of BYHWD used to treat ischemic stroke are not well understood. The current study aimed to identify the potential active components of BYHWD and explore its mechanism using network pharmacology and bioinformatics analyses. The compounds of BYHWD were obtained from public databases. Oral bioavailability and drug-likeness were screened using the absorption, distribution, metabolism and excretion (ADME) criteria. Components of BYHWD, alongside the candidate targets of each component and the known therapeutic targets of ischemic stroke were collected. A network of target gene compounds and cerebral ischemia compounds was established using network pharmacology data sources. The enrichment of key targets and pathways was analyzed using STRING and DAVID databases. Moreover, three of key targets [IL6, VEGFA and hypoxia-inducible-factor-1α (HIF-1α)] were verified using western blot analysis. Network analysis determined 102 compounds in seven herbal medicines that were subjected to ADME screening. A total of 42 compounds as well as 79 genes formed the principal pathways associated with ischemic stroke. The 16 key compounds identified were baicalein, beta-carotene, baicalin, kaempferol, luteolin, quercetin, hydroxysafflor yellow A, isorhamnetin, bifendate, formononetin, calycosin, astragaloside IV, stigmasterol, sitosterol, Z-ligustilide, and dihydrocapsaicin. The core genes in this network were IL6, TNF, VEGFA, HIF-1α, MAPK1, MAPK3, JUN, STAT3, IL1B and IL10. Furthermore, the TNF, IL17, apoptosis, PI3K-Akt, toll-like receptor, MAPK, NF-κB and HIF-1 signaling pathways were identified to be associated with ischemic stroke. Compared with the control group (no treatment), BYHWD significantly inhibited the expression of IL6 and increase the expression of HIF-1α and VEGFA. Network pharmacology analyses can help to reveal close interactions between multi-components and multi-targets and enhance understanding of the potential effects of BYHWD on ischemic stroke.

Salvia miltiorrhiza and the Volatile of Dalbergia odorifera Attenuate Chronic Myocardial Ischemia Injury in a Pig Model: A Metabonomic Approach for the Mechanism Study.

Salvia miltiorrhiza (SM) coupled with Dalbergia odorifera (DO) has been used to relieve cardiovascular diseases in China for many years. Our previous studies have integrated that SM-the volatile oil of DO (SM-DOO)-has a cardioprotective effect on chronic myocardial ischemia based on a pharmacological method, but the cardioprotective mechanism has not been elucidated completely in the metabonomic method. In the present study, a metabonomic method based on high-performance liquid chromatography time-of-flight mass spectrometry (HPLC-Q-TOF-MS) was performed to evaluate the effects of SM-DOO on chronic myocardial ischemia induced by an ameroid constrictor, which was placed on the left anterior descending coronary artery (LAD) of pigs. Pigs were divided into three groups: sham, model, and SM-DOO group. With multivariate analysis, a clear cluster among the different groups was obtained and the potential biomarkers were recognized. These biomarkers were mainly related to energy metabolism, glucose metabolism, and fatty acid metabolism. Furthermore, the protein expressions of phosphorylated AMP-activated protein kinase (p-AMPK) and glucose transporter-4 (GLUT4) were significantly upregulated by SM-DOO. The result indicated that SM-DOO could regulate the above biomarkers and metabolic pathways, especially energy metabolism and glucose metabolism. By analyzing and verifying the biomarkers and metabolic pathways, further understanding of the cardioprotective effect of SM-DOO with its mechanism was evaluated. Metabonomic is a reliable system biology approach for understanding the cardioprotective effects of SM-DOO on chronic myocardial ischemia and elucidating the mechanism underlying this protective effect.

A Network Pharmacology Approach to Predict the Proangiogenesis Mechanism of Huangqi-Honghua Herb Pair after Cerebral Ischemia.

OBJECTIVE: Huangqi-Honghua herb pair is known for its medicinal value to treat Qi deficiency and blood stasis syndrome with a long history in clinical practice. To understand its possible mechanism in a systematic study, a network pharmacological method was addressed. METHODS: Detailed information on the HH compounds was obtained from two public databases, and oral bioavailability (OB) and drug-like (DL) of the compounds were evaluated. A correlation between HH compounds, its potential targets, and known targets was extrapolated, and the herb-compound-target-disease (H-C-T-D) network was established. Next, the pathway enrichment and essential genes were analyzed. Then, three key genes (VEGFA, VEGFR2, and eNOS), highly associated with angiogenesis, were screened and verified through western blot assay. RESULTS: Out of 276 compounds, 21 HH compounds and 78 target genes regulating the major pathways associated with CI in the network are analyzed. The bioactive compounds in HH were active in various signal transduction pathways such as the toll-like receptor signaling pathway, VEGF signaling pathway, TNF signaling pathway, and HIF-1 signaling pathway are important pathways that may regulate anti-inflammatory, antiapoptotic, immune correlation, and antioxidative effects. The core genes are PTGS2, TNF, NOS2, IL6, BCL2, IL1B, SOD2, NOS3, SOD1, MMP9, and VEGFA. The in vitro results suggested that HH treatment could significantly elevate the expression of proangiogenic genes such as VEGFA, VEGFR2, and eNOS compared with OGD groups. CONCLUSIONS: Our results predict that HH may regulate the expression of VEGFA, VEGFR2, and eNOS via the VEGF and HIF-1 signaling pathway to promote angiogenesis and alleviate cerebral ischemia injury.

IRS-2/Akt/GSK-3ß/Nrf2 Pathway Contributes to the Protective Effects of Chikusetsu Saponin IVa against Lipotoxicity.

Chronic hyperlipidemia leads to pancreatic ß-cell apoptosis and dysfunction through inducing oxidative stress. Chikusetsu saponin IVa (CHS) showed antioxidant and antidiabetic properties in our previous studies; however, its protective effects against lipotoxicity-induced ß-cell oxidative stress and dysfunction are not clear. This study was designed to investigate the effects of CHS against lipotoxicity-induced ß-cell injuries and its possible mechanism involved. High-fat (HF) diet and a low dose of streptozotocin- (STZ-) induced type 2 diabetes mellitus (T2DM) model in vivo and ßTC3 cells subjected to 0.5 mM palmitate (PA) to imitate the lipotoxic model in vitro were performed. Pancreatic functions, ROS, and antioxidant protein measurements were performed to evaluate the effects of CHS on cell injuries. Protein expression levels were measured by Western blotting. Furthermore, siRNA-targeted Nrf2, PI3K/Akt inhibitor (LY294002), or GSK-3ß inhibitor (LiCl) was used to investigate the crosstalk relationships between proteins. As the results showed, CHS treatment inhibited apoptosis, promoted insulin release, and reduced oxidative stress. CHS treatment significantly increased the expression of Nrf2 in the cytoplasm and nuclear protein. The antioxidative and benefit effects of CHS were inhibited by siNrf2. The phosphorylation of IRS-2, PI3K, Akt, and GSK-3ß was markedly increased by CHS which were inhibited by PA. In addition, inhibition of PI3K/Akt or GSK-3ß with specific inhibitors dramatically abrogated the protective effects of CHS, revealing that the IRS-2/Akt/GSK-3ß signaling axis was involved in the protective effects of CHS. These results demonstrate that CHS protected ßTC3 cells against PA-induced oxidative stress and cell dysfunction through Nrf2 by the IRS-2/Akt/GSK-3ß-mediated pathway.

High expression of ISG20 predicts a poor prognosis in acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is one of the most malignant hematopoietic system diseases. Interferon stimulated exonuclease gene 20 (ISG20) is a protein induced by interferons or double-stranded RNA, which is associated with poor prognosis in several malignant tumors. However its expression in AML is unknown. OBJECTIVE: To explore the expression of ISG20 in AML and its prognostic significance. METHODS: The expression of ISG20 in AML patients was analyzed by GEPIA database, detected by qRT-PCR and their prognosis was followed-up. Chi-square test was used to identify the association between ISG20 expression and clinical characteristics of the patients. Kaplan-Meier analysis was performed to draw survival curves and Cox regression analysis to confirm the independent prognostic factors of AML patients. RESULTS: Kaplan-Meier analysis revealed that whether to receive treatment, karyotype, and ISG20 expression were related to overall survival time of AML patients (P< 0.05). Cox regression analysis showed that whether to receive treatment (HR = 0.248, 95% CI = 0.076-0.808, P= 0.021) and high expression of ISG20 (HR = 4.266, 95% CI = 1.118-16.285, P= 0.034) were independent unfavorable prognostic factors for AML patients. CONCLUSION: The high expression of ISG20 acts as a poor prognosis indicator in AML patients.

Effects of Shuanghuanglian oral liquids on patients with COVID-19: a randomized, open-label, parallel-controlled, multicenter clinical trial.

We conducted a randomized, open-label, parallel-controlled, multicenter trial on the use of Shuanghuanglian (SHL), a traditional Chinese patent medicine, in treating cases of COVID-19. A total of 176 patients received SHL by three doses (56 in low dose, 61 in middle dose, and 59 in high dose) in addition to standard care. The control group was composed of 59 patients who received standard therapy alone. Treatment with SHL was not associated with a difference from standard care in the time to disease recovery. Patients with 14-day SHL treatment had significantly higher rate in negative conversion of SARS-CoV-2 in nucleic acid swab tests than the patients from the control group (93.4% vs. 73.9%, P = 0.006). Analysis of chest computed tomography images showed that treatment with high-dose SHL significantly promoted absorption of inflammatory focus of pneumonia, which was evaluated by density reduction of inflammatory focus from baseline, at day 7 (mean difference (95% CI), -46.39 (-86.83 to -5.94) HU; P = 0.025) and day 14 (mean difference (95% CI), -74.21 (-133.35 to -15.08) HU; P = 0.014). No serious adverse events occurred in the SHL groups. This study illustrated that SHL in combination with standard care was safe and partially effective for the treatment of COVID-19.

A splicing LMNA mutation causing laminopathies accompanied by aortic valve malformation.

BACKGROUND: Laminopathies caused by LMNA gene mutations are characterized by different clinical manifestations. Among them, cardiac involvement is one of the most severe phenotypes. CASE PRESENTATION: A 30-year-old man visited the hospital because of palpitations, shortness of breath, and fatigue. He also had muscular dystrophy, joint contractures, scoliosis, and mild dysphagia. A novel de novo heterozygous LMNA splice variant (c.810+1G>T) with dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy, and progressive cardiac conduction defect was identified by genetic analysis. The patient also presented with congenital aortic valve malformation, which has never been reported in laminopathies. CONCLUSIONS: The LMNA mutation (c.810+1G>T) was identified for the first time, enriching the mutation spectrum of the LMNA gene. The correlation between an LMNA mutation and congenital aortic valve malformation deserves further study.

Astragaloside and/or Hydroxysafflor Yellow A Attenuates Oxygen-Glucose Deprivation-Induced Cultured Brain Microvessel Endothelial Cell Death through Downregulation of PHLPP-1.

The incidence of ischemic stroke, a life-threatening condition in humans, amongst Asians is high and the prognosis is poor. In the absence of effective therapeutics, traditional Chinese medicines have been used that have shown promising results. It is crucial to identify traditional Chinese medicine formulas that protect the blood-brain barrier, which is damaged by an ischemic stroke. In this study, we aimed to elucidate such formulas. Brain microvascular endothelial cells (BMECs) were used to establish an in vitro ischemia-reperfusion model for oxygen-glucose deprivation (OGD) experiments to evaluate the function of two traditional Chinese medicines, namely, astragaloside (AS-IV) and hydroxysafflor yellow A (HSYA), in protecting against BMEC. Our results revealed that AS-IV and HSYA attenuated the cell loss caused by OGD by increasing cell proliferation and inhibiting cell apoptosis. In addition, these compounds promoted the migration and invasion of BMECs in vitro. Furthermore, we found that BMECs rescued by AS-IV and HSYA could be functionally activated in vitro, with AS-IV and HSYA showing synergetic effects in rescuing BMECs survival in vitro by reducing the expression of PHLPP-1 and activating Akt signaling. Our results elucidated the potential of AS-IV and HSYA in the prevention and treatment of stroke by protecting against cerebral ischemia-reperfusion injury.

Chrysophanol ameliorates renal interstitial fibrosis by inhibiting the TGF-ß/Smad signaling pathway.

Renal interstitial fibrosis (RIF) is a major pathological feature of chronic kidney disease at middle and end stages. Chrysophanol (CP), 1,8-dihydroxy-3-methyl-9,10-anthraquinone, is an anthraquinone isolated from Rheum palmatum L. with a variety of pharmacological activities including the suppression of RIF. However, the effect of CP on renal fibrosis and its potential mechanism have not been elucidated. We conducted a comprehensive study by determining the expression levels of fibrotic markers and proteins including TGF-ß1, α-SMA, and Smad3 related to transforming growth factor-beta/Smad (TGF-ß/Smad) pathway in unilateral ureteral obstruction (UUO) mice and TGF-ß1-stimulated HK-2 cells with the treatment of CP using western blotting and RT-qPCR analyses. Using small interfering RNA and co-immunoprecipitation, we evaluated the influences of CP on the interactions between Smad3 and Smad7 proteins and also on TGF-ß RI and TGF-ßR II. We found that CP administration significantly ameliorated UUO-induced kidney damage by reversing abnormal serum and urine biochemical parameters and decreasing the production of fibrotic markers including collagen I, collagen III, fibronectin, and α-SMA. Our results showed that TGF-ß1 and phospho-Smad3 (p-Smad3) expression was significantly down-regulated and Smad7 expression was up-regulated by CP in UUO mice compared to the model group; however, the expression of Smad2, Smad4, and TGF-ß receptors was not affected. Furthermore, CP modulated these fibrotic markers as well as p-Smad3 and Smad7 in TGF-ß1-induced HK-2 cells. The inhibitory effect of CP was markedly reduced in TGF-ß1-treated HK-2 cells transfected with Smad3 siRNA. Additionally, co-immunoprecipitation analysis indicated that CP blocked the interaction between Smad3 and TGF-ß receptor I to suppress p-Smad3 expression. These findings demonstrated that CP alleviated RIF by inhibiting Smad3 phosphorylation, which provides a molecular basis for a new drug candidate for the treatment of RIF.

Renal protection of rhein against 5/6 nephrectomied-induced chronic kidney disease: role of SIRT3-FOXO3α signalling pathway.

OBJECTIVES: The purpose of this study is to investigate the antifibrosis and anti-oxidation of rhein in vivo and in vitro, and to evaluate potential mechanisms involved in the treatment of chronic kidney disease (CKD). METHODS: In experimental animal studies, CKD was established by 5/6 nephrectomy (5/6Nx). Serum creatinine (Scr) and blood urea nitrogen (BUN) were determined. Histopathologic tests were performed by HE and Masson trichrome stained. The level of ROS was investigated by fluorescence microplate with the probe 2', 7'-dichlorofluorescein diacetate (DCFH-DA). The protein expressions of p47phox and gp91phox were measured in 5/6Nx rats. In HK-2 cells, the expression of SIRT3 and Foxo3α was measured in SIRT3 knockdown conditions. The indicators of oxidation and fibrosisi were measured in SIRT3 knockdown conditions. KEY FINDINGS: The results showed that, in addition to reducing renal interstitial pathologic injury and collagen fibrils, rhein administration improved renal function. The protective mechanisms were attributed to active SIRT3/FOXO3α signalling pathway and then play the anti-oxidative capacity of rhein, as well as to subsequent antifibrotic effect. CONCLUSION: Taken together, rhein protected kidney through SIRT3/FOXO3a involvement. The anti-oxidative capacity of rhein contributed to the protective effects including the subsequent antifibrotic responses.