Safety, immunogenicity, and efficacy of a modified COVID-19 mRNA vaccine, SW-BIC-213, in healthy people aged 18 years and above: a phase 3 double-blinded, randomized, parallel controlled clinical trial in Lao PDR (Laos).

Background: The mRNA vaccine has demonstrated significant effectiveness in protecting against SARS-CoV-2 during the pandemic, including against severe forms of the disease caused by emerging variants. In this study, we examined safety, immunogenicity, and relative efficacy of a heterologous booster of the lipopolyplex (LPP)-based mRNA vaccine (SW-BIC-213) versus a homologous booster of an inactivated vaccine (BBIBP) in Laos. Methods: In this phase 3 clinical trial, which was randomized, parallel controlled and double-blinded, healthy adults aged 18 years and above were recruited from the Southern Savannakhet Provincial Hospital and Champhone District Hospital. The primary outcomes were safety and immunogenicity, with efficacy as an exploratory endpoint. Participants who were fully immunized with a two-dose inactivated vaccine for more than 6 months were assigned equally to either the SW-BIC-213 group (25 µg) or BBIBP group. The primary safety endpoint was to describe the safety profile of all participants in each group up to 6 months post-booster immunization. The primary immunogenic outcome was to demonstrate the superiority of the neutralizing antibody response, in terms of geometric mean titers (GMTs) of SW-BIC-213, compared with BBIBP 28 days after the booster dose. The exploratory efficacy endpoint aimed to assess the relative efficacy of SW-BIC-213 compared to BBIBP against virologically confirmed symptomatic COVID-19 over a 6-month period. The trial was registered with ClinicalTrials.gov (NCT05580159). Findings: Between October 10, 2022, and January 13, 2023, 1200 participants were assigned to SW-BIC-213 group and 1203 participants in the BBIBP group. All adverse reactions observed during the study were tolerable, transient, and resolved spontaneously. Solicited local reactions were the main adverse reactions in both the SW-BIC-213 group (43.8%) and BBIBP group (14.8%) (p < 0.001). Heterologous boosting with SW-BIC-213 induced higher live virus neutralizing antibodies to SARS-CoV-2 wildtype and BA.5 strains with GMTs reaching 750.1 and 192.9 than homologous boosting with BBIBP with GMTs of 131.5 (p < 0.001) and 47.5 (p < 0.001) on day 29. The statistical findings revealed that, following a period of 14-day to 6-month after booster vaccination, the SW-BIC-213 group exhibited a relative vaccine efficacy (VE) of 70.1% (95% CI: 34.2-86.4) against symptomatic COVID-19 when compared to the BBIBP group. Interpretation: A heterologous booster with the COVID-19 mRNA vaccine SW-BIC-213 manifests a favorable safety profile and proves highly immunogenic and efficacious in preventing symptomatic COVID-19 in individuals who have previously received two doses of inactivated vaccine. Funding: Shanghai Strategic Emerging Industries Development Special Fund, Biomedical Technology Support Special Project of Shanghai "Science and Technology Innovation Action Plan", Shanghai Municipal Science and Technology Commission.

Multi-dimensional metabolomic profiling reveals dysregulated ornithine metabolism hallmarks associated with a severe acute pancreatitis phenotype.

To reveal dysregulated metabolism hallmark that was associated with a severe acute pancreatitis (SAP) phenotype. In this study, LC-MS/MS-based targeted metabolomics was used to analyze plasma samples from 106 acute pancreatitis (AP) patients (34 mild, 38 moderate, and 34 severe) admitted within 48 hours from abdominal pain onset and 41 healthy controls. Temporal metabolic profiling was performed on days 1, 3, and 7 after admission. A random forest (RF) was performed to significantly determine metabolite differences between SAP and non-SAP (NSAP) groups. Mass spectrometry imaging (MSI) and immunohistochemistry were conducted for the examination of pancreatic metabolite and metabolic enzyme alterations, respectively, on necrosis and paracancerous tissues. Simultaneously determination of serum and pancreatic tissue metabolic alterations using an L-ornithine-induced AP model to discover metabolic commonalities. Twenty-two significant differential metabolites screened by RF were selected to build an accurate model for the prediction of SAP from NSAP (AUC = 0.955). Six of 22 markers were found by MSI with significant alterations in pancreatic lesions, reduced ornithine-related metabolites were also identified. The abnormally expressed arginase2 and ornithine transcarboxylase were further discovered in combination with time-course metabolic profiling in the SAP animal models, the decreased ornithine catabolites were found at a late stage of inflammation, but ornithine-associated metabolic enzymes were activated during the inflammatory process. The plasma metabolome of AP patients is distinctive, which shows promise for early SAP diagnosis. AP aggravation is linked to the activated ornithine metabolic pathway and its inadequate levels of catabolites in in-situ lesion.

Effect of Mechanical Ventilation Mode Type on Postoperative Pulmonary Complications After Cardiac Surgery: A Randomized Controlled Trial.

OBJECTIVES: It is unknown whether there is a difference in pulmonary outcome in different intraoperative ventilation modes for cardiac surgery with cardiopulmonary bypass (CPB). The aim of this trial was to determine whether patients undergoing cardiac surgery with CPB could benefit from intraoperative optimal ventilation mode. DESIGN: This was a single-center, prospective, randomized controlled trial. SETTING: The study was conducted at a single-center tertiary-care hospital. PARTICIPANTS: A total of 1,364 adults undergoing cardiac surgery with CPB participated in this trial. INTERVENTIONS: Patients were assigned randomly (1:1:1) to receive 1 of 3 ventilation modes: volume-controlled ventilation (VCV), pressure-controlled ventilation (PCV), and pressure-controlled ventilation-volume guaranteed (PCV-VG). All arms of the study received the lung-protective ventilation strategy. MEASUREMENTS AND MAIN RESULTS: The primary outcome was a composite of postoperative pulmonary complications (PPCs) within the first 7 postoperative days. Pulmonary complications occurred in 168 of 455 patients (36.9%) in the PCV-VG group, 171 (37.6%) in the PCV group, and 182 (40.1%) in the VCV group, respectively. There was no statistical difference in the risk of overall pulmonary complications among groups (p = 0.585). There were no significant differences in the severity grade of PPCs within 7 days, postoperative ventilation duration, intensive care unit stay, postoperative hospital stay, or 30-day postoperative mortality. CONCLUSIONS: Among patients scheduled for cardiac surgery with CPB, intraoperative ventilation mode type did not affect the risk of postoperative pulmonary complications.

Phase I study of a non-S2P SARS-CoV-2 mRNA vaccine LVRNA009 in Chinese adults.

BACKGROUND: COVID-19 caused by SARS-CoV-2 is a great threat to public health. We present the safety and immunogenicity data from a phase I trial in China of an mRNA vaccine (LVRNA009). METHODS: In the single-centre, double-blind, placebo-controlled and dose-escalation study, 72 healthy unvaccinated adults aged 18-59 years were randomized (3:1) to receive LVRNA009 with one of three vaccine dosage (25, 50 and 100 µg) or placebo, to evaluate for the safety, tolerability and immunogenicity of LVRNA009. RESULTS: All these participants received two injections 28 days apart. No adverse events higher than grade 2 were reported during the study. A total of 30 participants (42 %) reported solicited adverse reactions during the first 14 days after vaccinations. Of the events reported, fever (n = 11, 15 %) was the most common systemic adverse reaction, and pain at the injection site (n = 17, 24 %) was the most frequent solicited local adverse reaction. Anti-S-protein IgG and neutralising antibodies were observed to have been induced 14 days after the first dose, significantly increased 7 days after the second dose, and remained at a high level 28 days after the second dose. Specific T-cell responses peaked 7 days and persisted 28 days after second vaccination. CONCLUSION: LVRNA009 has demonstrated promising results in safety and tolerability at all three dose levels among Chinese adults. LVRNA009 at three dose levels could rapidly induce strong humoral and cellular immune responses, including binding and neutralising antibody production and IFN- γ secretion, which showed good immunogenicity. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT05364047; Chictr.org.cn ChiCTR2100049349.

Tectorigenin: A Review of Its Sources, Pharmacology, Toxicity, and Pharmacokinetics.

Tectorigenin is a well-known natural flavonoid aglycone and an active component that exists in numerous plants. Growing evidence suggests that tectorigenin has multiple pharmacological effects, such as anticancer, antidiabetic, hepatoprotective, anti-inflammatory, antioxidative, antimicrobial, cardioprotective, and neuroprotective. These pharmacological properties provide the basis for the treatment of many kinds of illnesses, including several types of cancer, diabetes, hepatic fibrosis, osteoarthritis, Alzheimer's disease, etc. The purpose of this paper is to provide a comprehensive summary and review of the sources, extraction and synthesis, pharmacological effects, toxicity, pharmacokinetics, and delivery strategy aspects of tectorigenin. Tectorigenin may exert certain cytotoxicity, which is related to the administration time and concentration. Pharmacokinetic studies have demonstrated that the main metabolic pathways in rats for tectorigenin are glucuronidation, sulfation, demethylation and methoxylation, but that it exhibits poor bioavailability. From our perspective, further research on tectorigenin should cover: exploring the pharmacological targets and mechanisms of action; finding an appropriate concentration to balance pharmacological effects and toxicity; attempting diversified delivery strategies to improve the bioavailability; and structural modification to obtain tectorigenin derivatives with higher pharmacological activity.

The effect of driving pressure-guided versus conventional mechanical ventilation strategy on pulmonary complications following on-pump cardiac surgery: A randomized clinical trial.

STUDY OBJECTIVE: Postoperative pulmonary complications occur frequently and are associated with worse postoperative outcomes in cardiac surgical patients. The advantage of driving pressure-guided ventilation strategy in decreasing pulmonary complications remains to be definitively established. We aimed to investigate the effect of intraoperative driving pressure-guided ventilation strategy compared with conventional lung-protective ventilation on pulmonary complications following on-pump cardiac surgery. DESIGN: Prospective, two-arm, randomized controlled trial. SETTING: The West China university hospital in Sichuan, China. PATIENTS: Adult patients who were scheduled for elective on-pump cardiac surgery were enrolled in the study. INTERVENTIONS: Patients undergoing on-pump cardiac surgery were randomized to receive driving pressure-guided ventilation strategy based on positive end-expiratory pressure (PEEP) titration or conventional lung-protective ventilation strategy with fixed 5 cmH2O of PEEP. MEASUREMENTS: The primary outcome of pulmonary complications (including acute respiratory distress syndrome, atelectasis, pneumonia, pleural effusion, and pneumothorax) within the first 7 postoperative days were prospectively identified. Secondary outcomes included pulmonary complication severity, ICU length of stay, and in-hospital and 30-day mortality. MAIN RESULTS: Between August 2020 and July 2021, we enrolled 694 eligible patients who were included in the final analysis. Postoperative pulmonary complications occurred in 140 (40.3%) patients in the driving pressure group and 142 (40.9%) in the conventional group (relative risk, 0.99; 95% confidence interval, 0.82-1.18; P = 0.877). Intention-to-treat analysis showed no significant difference between study groups regarding the incidence of primary outcome. The driving pressure group had less atelectasis than the conventional group (11.5% vs 17.0%; relative risk, 0.68; 95% confidence interval, 0.47-0.98; P = 0.039). Secondary outcomes did not differ between groups. CONCLUSION: Among patients who underwent on-pump cardiac surgery, the use of driving pressure-guided ventilation strategy did not reduce the risk of postoperative pulmonary complications when compared with conventional lung-protective ventilation strategy.

Elucidation of the interaction mechanism of olmutinib with human α-1 acid glycoprotein: insights from spectroscopic and molecular modeling studies.

Olmutinib, the third-generation tyrosine kinase inhibitor, is applied in treating non-small cell lung cancer (NSCLC). The aim of this study is to elucidate the interaction mechanism of olmutinib with human α-1 acid glycoprotein (HAG), an important carrier protein, by mean of multi-spectroscopic and molecular simulation techniques. Fluorescence spectral results confirmed that the fluorescence of this carrier protein can be quenched by olmutinib in the static quenching mode, and this anticancer drug possesses a moderate binding affinity on HAG. The evidence from thermodynamic analysis, replacement interaction with ANS and sucrose, and computational simulation results showed that hydrogen bonding, hydrophobic interactions, and van der Waals forces involved the olmutinib-HAG complexation process. The results from UV-vis, 3D fluorescence and synchronous fluorescence spectroscopy proved that binding anticancer drug olmutinib caused the alteration in the microenvironment around Trp residues. And, circular dichroism spectral results provided the support for the conformational alterations in the carrier protein. The data also proved that olmutinib preferably bound to the hydrophobic cavity of HAG and the binding distance between the two was 2.21 nm. In addition, it can be found that the presence of some metal ions such as Zn2+, Ca2+, Ni2+ and Cu2+ would exert a certain extent effect on the olmutinib-HAG complexation process.Communicated by Ramaswamy H. Sarma.

Organophosphorus flame retardant TDCPP induces neurotoxicity via mitophagy-related ferroptosis in vivo and in vitro.

Tris (1,3-dichloro-2-propyl) phosphate (TDCPP) has neurotoxicity, but its mechanism remains unclear. Evidence recently showed that ferroptosis might be associated with TDCPP-induced neurotoxicity. To explore the role and underlying mechanism of ferroptosis in TDCPP-induced neurotoxicity, the occurrence of ferroptosis was examined in mice and PC12 cells upon TDCPP exposure. The mechanism of TDCPP-induced ferroptosis was clarified in vitro combined with the RNA sequencing assay. The in vivo results showed that orally TDCPP exposure (100 mg/kg, 30 d) inhibited the learning and memory ability of mice, reduced hippocampus neurons, induced malondialdehyde (MDA) accumulation, and decreased glutathione (GSH) and superoxide dismutase (SOD) levels in the hippocampus. Moreover, TDCPP exposure (100 mg/kg, 30 d) altered the ferroptosis and autophagy-related protein abundances in the hippocampus. The in vitro results showed that TDCPP exposure (0, 5, 20, 50, 100, and 200 µM) for 24 h induced dose-dependent cell death in PC12 cells, and the cell death was ameliorated by the co-treatment with ferrostatin-1 (1 µM, 24 h). Similarly, TDCPP exposure (0, 50, 100, and 200 µM) for 24 h increased the levels of MDA and LPO, but decreased the reduced GSH in PC12 cells. Furthermore, TDCPP exposure (0, 50, 100, and 200 µM) for 24 h altered the ferroptosis and autophagy-related protein abundances in PC12 cells. The RNA-sequencing revealed that TDCPP exposure (100 µM, 24 h) induced mitophagy activation in SH-SY5Y cells. Meanwhile, the in vitro experiments confirmed that TDCPP exposure (0, 50, 100, and 200 µM) for 24 h increased abundances of mitophagy-related protein phosphatase and tensin homolog induced kinase 1(PINK1), Parkinson protein 2 E3 ubiquitin-protein ligase (PARKIN), inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), and voltage-dependent anion channel 1 (VDAC1) in PC12 cells. Moreover, TDCPP treatment (100 µM, 24 h) increased the mitochondrial recruitment of PARKIN, decreased the mitochondrial membrane potential (MMP) level, and increased the Fe2+ level in mitochondria. In addition, decreased ATP levels and increased reactive oxygen species (ROS) levels were observed in PC12 cells upon TDCPP exposure (0, 50, 100, and 200 µM) for 24 h. In summary, ferroptosis was associated with TDCPP-induced neurotoxicity, and the mechanism might be related to PINK1/PARKIN-mediated mitophagy initiated by mitochondrial damage.

Efficacy of heterologous boosting against SARS-CoV-2 using a recombinant interferon-armed fusion protein vaccine (V-01): a randomized, double-blind and placebo-controlled phase III trial.

Waning of neutralizing titres along with decline of protection efficacy after the second dose of COVID-19 vaccines was observed, including China-made inactivated vaccines. Efficacy of a heterologous boosting using one dose of a recombinant SARS-CoV-2 fusion protein vaccine (V-01) in inactivated vaccine-primed population was studied, aimed to restore the immunity. A randomized, double-blind and placebo-controlled phase III trial was conducted in healthy people aged 18 years or older in Pakistan and Malaysia. Each eligible participant received one dose of the V-01 vaccine developed by Livzon Mabpharm Inc. or placebo within the 3-6 months after the two-dose primary regimen, and was monitored for safety and efficacy. The primary endpoint was protection against confirmed symptomatic SARS-CoV-2 infection. A total of 10,218 participants were randomly assigned to receive a vaccine or placebo. Virus-neutralizing antibodies were assessed in 419 participants. A dramatic increase (11.3-fold; 128.3-1452.8) of neutralizing titres was measured in the V-01 group at 14 days after the booster. Over two months of surveillance, vaccine efficacy was 47.8% (95%CI: 22.6-64.7) according to the intention-to-treat principle. The most common adverse events were transient, mild-to-moderate pain at the injection site, fever, headache, and fatigue. Serious adverse events occurred almost equally in V-01 (0.12%) and placebo (0.16%) groups. The heterologous boosting with the V-01 vaccine was safe and efficacious, which could elicit robust humoral immunity under the epidemic of the Omicron variant.Trial registration: ClinicalTrials.gov identifier: NCT05096832.

Change and impact of left ventricular global longitudinal strain during transcatheter aortic valve implantation.

BACKGROUND: Although transcatheter aortic valve implantation (TAVI) is a safe and effective treatment for aortic stenosis, it still carries some risks, such as valve leaks, stroke, and even death. The left ventricular global longitudinal strain (LVGLS) measurement may be useful for the prediction of adverse events during this operation. AIM: To explore the change of LVGLS during TAVI procedure and the relationship between LVGLS and perioperative adverse events. METHODS: In this study, 61 patients who had undergone percutaneous transfemoral TAVI were evaluated by transthoracic echocardiography. Before surgery, data on left ventricular ejection fraction (LVEF) and LVGLS were collected separately following balloon expansion and stent implantation. Difference in values of LVGLS and LVEF during preoperative balloon expansion (pre-ex), preoperative stent implantation (pre-im) and balloon expansion-stent implantation (ex-im) were also examined. Adverse events were defined as perioperative death, cardiac rupture, heart arrest, moderate or severe perivalvular leakage, significant mitral regurgitation during TAVI, perioperative moderate or severe mitral regurgitation, perioperative left ventricular outflow tract obstruction, reoperation, and acute heart failure. RESULTS: The occurrence of perioperative adverse events was associated with differences in pre-ex LVGLS, but not with difference in pre-ex LVEF. There were significant differences between pre-LVGLS and ex-LVGLS, and between pre-LVGLS and im-LVGLS (P = 0.037 and P = 0.020, respectively). However, differences in LVEF were not significant (P = 0.358, P = 0.254); however differences in pre-ex LVGLS were associated with pre-LVGLS (P = 0.045). Compared to LVEF, LVGLS is more sensitive as a measure of left heart function during TAVI and the perioperative period. Moreover, the differences in LVGLS were associated with the occurrence of perioperative adverse events, and changes in LVGLS were apparent in patients with undesirable LVGLS before the surgery. Furthermore, LVGLS is useful to predict changes in cardiac function during TAVI. CONCLUSION: Greater attention should be paid to the patients who plan to undergo TAVI with normal LVEF but poor LVGLS.

Registration of intervention trials of Traditional Chinese Medicine for four neurological diseases on Chinese Clinical Trial Registry and ClinicalTrials.gov: a narrative review.

OBJECTIVE: To analyze the current status of clinical trial registration of Traditional Chinese Medicine (TCM) for the treatment of neurological diseases. METHODS: Interventional clinical trials of TCM treatment for ischemic stroke, hemorrhagic stroke, vascular cognitive impairment, tension-type headache before September 22, 2020 on the platform of Chinese Clinical Trial Registry (ChiCTR), and ClinicalTrials.gov were searched. Two researchers independently selected the literature and extracted data. RESULTS: A total of 180 interventional clinical trials were included for analysis. Out of 180 trials, 127 were from ChiCTR and 53 from ClinicalTrials.gov. The countries primary sponsoring the included trials were China (176, 97.8%), and the common categories of primary sponsors were hospital (131, 72.8%). Among the study design, the largest proportion of allocation was randomized (172, 95.6%), interventional model assignment was parallel (163, 90.6%), masking was double blind 49 (27.2%), and the sample size was ≤ 400 (144, 80.0%). The trials were most carried out at a single center (102, 56.7%). Among the included studies, 112 (62.2%) registered on ChiCTR attached the ethical approval documents. In terms of trial stages, 50 (27.7%) studies were in phase IV. The mostly used intervention was Chinese herbal medicines (99, 55%), acupuncture (68, 37.8%) was the second. By searching the registration number on China National Knowledge Infrastructure Database and PubMed, 38 (21.1%) registered trials were published, including 25 protocol studies and 14 research results with one (NCT02275949) published both the protocol and the results. CONCLUSIONS: Irregular and inadequate reporting, untimely update and publication, insufficient information on traditional medicine unique characteristics, and lack of international collaborations are the problems existing in the interventional clinical registration trials of traditional medicine treatment on neurological diseases. More efforts need to be made from the above aspects to standardize and improve the registration of traditional medicine trials.

Whole-exome sequencing facilitates the differential diagnosis of Ehlers-Danlos syndrome (EDS).

Ehlers-Danlos syndromes (EDSs) are a group of rare monogenic conditions with strong heterogeneity and can be caused by 20 genes associating with the essence of the extracellular matrix (ECM). This study enrolled three cases with various subtypes of EDS. Clinical evaluation and genetic testing with whole-exome sequencing (WES) were performed. The clinical manifestations of all three patients were thoroughly monitored; and three de novo diagnostic variants, namely COL5A1: NM_001278074.1: c.4609-2A>C, COL3A1: NM_000090.3: c.3554G>T(p.Gly1185Val), and COL1A1: NM_000088.3: c.545G>T(p.Gly182Val) were identified from them, respectively. The findings in this study expanded the mutation spectrum of EDS and strengthened the efficiency of WES in the differential diagnosis on disorders with overlapping phenotypes and various pathogenesis.

[Expert consensus on clinical application of Compound Congrong Yizhi Capsules in treatment of vascular dementia].

Compound Congrong Yizhi Capsules is widely used in clinic for the long-term treatment and synergistic treatment of vascular cognitive impairment. After years of clinical observation, it has an obvious curative effect on the treatement of vascular cognitive impairment and has been recommended by multiple guidelines, consensuses, and series. This consensus was formulated for the treatment of vascular dementia. On the basis of summarizing the application experience of clinicians, and combined with the existing evidence-based evidence, 11 recommendations/consensus recommendations were finally reached through the nominal group method. The indications, usage and dosage, course of treatment, medication time, concomitant medication, and precautions of Congrong Yizhi Capsules in the treatment of vascular dementia were proposed, and the safety of the clinical application was described. This consensus is applicable to the use of Compound Congrong Yizhi Capsules in the treatment of patients with vascular dementia, and can be used by clinicians from the departments of encephalopathy(neurology), geriatrics, and traditional Chinese medicine in general hospitals. This consensus has been approved by China Association of Chinese Medicine, with the number of GS/CACM 298-2022.

Acetylation of H3K27 activated lncRNA NEAT1 and promoted hepatic lipid accumulation in non-alcoholic fatty liver disease via regulating miR-212-5p/GRIA3.

Non-alcoholic fatty liver disease (NAFLD) was a world-wide health burden. H3K27 acetylation, long non-coding RNA (lncRNA), and miRNA were all implicated in NAFLD regulation, yet the detailed regulatory mechanism was not well understood. LncRNA NEAT1, miR-212-5p, and GRIA3 expression were detected both in high fatty acid-treated hepatocytes cells and NAFLD patients. Lipid droplets were stained and analyzed by oil red O staining. Expression of fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), and GRIA3 was detected by qRT-PCR and western blot. RNA level of lncRNA NEAT1 and miR-212-5p was analyzed by qRT-PCR. The binding sequences of lncRNA NEAT1/miR-212-5p and miR-212-5p/GRIA3 were predicted bioinformatically and validated through luciferase assay. ChIP was performed to analyze H3K27 acetylation on the promoter of lncRNA NEAT1. LncRNA NEAT1 and GRIA3 was upregulated, while miR-212-5p was downregulated in NAFLD patients. FFA promoted lncRNA NEAT1 and GRIA3 expression while suppressing miR-212-5p and promoted lipid accumulation as indicated by increased oil red O staining and FAS and ACC expression. ChIP indicated enrichment of H3K27 on NEAT1 promoter. Inhibition of H3K27 acetylation suppressed lncRNA NEAT1 level. Luciferase results indicated direct interaction of NEAT1/miR-212-5p (which was confirmed by RIP) and miR-212-5p/GRIA3. LncRNA NEAT1 knockdown upregulated miR-212-5p level and inhibited FFA-induced lipid accumulation while suppressing GRIA3 expression. Such function was antagonized by miR-212-5p inhibition and GRIA3 knockdown counteracted with miR-212-5p inhibition. H3K27 acetylation was enriched within the promoter of lncRNA NEAT1 and promoted lncRNA NEAT1 transcription. LncRNA NEAT1 could then interact with miR-212-5p and suppress its cellular concentration.

Type II Alexander disease with fragile X mental retardation 1 gene mutation.

Alexander disease (AxD) is a rare, autosomal dominant genetic disorder with an incidence of approximately 1 in 27,00.000. It is caused by a missense mutation in the GFAP gene encoding the glial fibrillary acidic protein. Fragile X-associated tremor/ataxia syndrome (FXTAS) is an X-linked dominant genetic disease, usually caused by a pre-mutation: an unmethylated expansion in the range of 50-200 CGG repeats in the fragile X mental retardation 1 (FMR1) gene. The clinical manifestations of these two diseases are complex and have some similarities. Both type II AxD and FXTAS may have ataxia as the first symptom. Here, we describe a case of type II AxD with ataxia as the first symptom accompanying a hemizygous mutation in the FMR1 gene (NM_001185081, exon13, c 0.1256C>T, p.T419M, g 0.147026507C>T). A sporadic genetic mutation led us to misdiagnose the patient with FXTAS initially. Whole-genome sequencing confirmed a heterozygous mutation in the GFAP gene (NM_002055.5, exon4, c 0.1158C>A, p.N386K, g 0.6310C>A). This report indicates that when the patient's clinical manifestation is ataxia, and imaging results suggest that the midbrain, medulla oblongata, and other subcerebellar structures are atrophied, AxD should be considered. Whole-genome sequencing is thus feasible to avoid missed diagnoses and misdiagnoses.

Novel pectin from crude polysaccharide of Syzygium aromaticum against SARS-CoV-2 activities by targeting 3CLpro

To date, COVID-19 is still a severe threat to public health, hence specific effective therapeutic drugs development against SARS-CoV-2 is urgent needed. 3CLpro and PLpro and RdRp are the enzymes required for the SARS-CoV-2 RNA synthesis. Therefore, binding to the enzyme may interfere the enzyme function. Before, we found that sulfated polysaccharide binding to 3CLpro might block the virus replication. Hence, we hypothesize that negative charged pectin glycan may also impede the virus replication. Here we show that 922 crude polysaccharide from Syzygium aromaticum may near completely block SARS-CoV-2 replication. The inhibition rate was 99.9% (EC50 : 0.90 M). Interestingly, 922 can associates with 3CLpro, PLpro and RdRp. We further show that the homogeneous glycan 922211 from 922 may specifically attenuate 3CL protease activity. The IC50s of 922 and 922211 against 3CLpro are 4.73 {+/-} 1.05 {micro}M and 0.18 {+/-} 0.01 {micro}M, respectively. Monosaccharide composition analysis reveals that 922211 with molecular weight of 78.7 kDa is composed of rhamnose, galacturonic acid, galactose and arabinose in the molar ratio of 8.21 : 37.81 : 3.58 : 4.49. The structure characterization demonstrated that 922211 is a homogalacturonan linked to RG-I pectin polysaccharide. The linear homogalacturonan part in the backbone may be partly methyl esterified while RG-I type part bearing 1, 4-linked -GalpA, 1, 4-linked -GalpAOMe and 1, 2, 4-linked -Rhap. There are four branches attached to C-1 or C4 position of Rhamnose glycosyl residues on the backbone. The branches are composed of 1, 3-linked {beta}-Galp, terminal (T)-linked {beta}-Galp, 1, 5-linked -Araf, T-linked -Araf, 4-linked -GalpA and/or 4-linked {beta}-GalpA. The above results suggest that 922 and 922211 might be a potential novel leading compound for anti-SARS-CoV-2 new drug development.

Therapeutic Targets and Mechanism of Xingpi Jieyu Decoction in Depression: A Network Pharmacology Study.

BACKGROUND: Depression is a common mental disease that lacks effective therapeutic drugs with good curative effects and few adverse reactions. Traditional Chinese medicine (TCM) has the advantages of multiple components, multiple channels, and fewer adverse reactions in the treatment of depression. Although Xingpi Jieyu Decoction (XPJYD) demonstrates a good therapeutic effect on depression, the pharmacological mechanism underlying its antidepressant effect is still unclear. METHODS: We used a network pharmacology strategy, including the construction and analysis of a complex drug-disease network, to explore the complex mechanism of XPJYD treatment of depression. In addition, molecular docking technology was used to preliminarily study the binding ability of the potential active components and core therapeutic targets of XPJYD. RESULTS: The network pharmacology results showed 42 targets of XPJYD that are involved in depression. PPI network analysis demonstrated that the top 10 core targets were AKT1, VEGFA, MAPK8, FOS, ESR1, NR3C1, IL6, HIF1A, NOS3, and AR. The molecular docking results showed that the binding energies of beta sitosterol with AR, FOS, AKT1, VEGFA, NR3C1, and NOS3 were less than -7.0 kcal·mol-1, indicating a good docking effect. The GO enrichment analysis results showed that the XPJYD antidepression mechanism mainly involves the following biological processes such as apoptotic signaling pathway, cellular response to lipid, inflammatory response, and others. The KEGG analysis results indicated that XPJYD may regulate 13 pathways such as PI3K-Akt signaling pathway and estrogen signaling pathway in the treatment of depression. CONCLUSIONS: This study reflects the characteristics of the mechanism of action by which XPJYD treats depression, which includes multiple components, multiple targets, and multiple pathways, and provides a biological basis for further verification and a novel perspective for drug discovery in depression.

Immunogenicity and safety of a recombinant fusion protein vaccine (V-01) against coronavirus disease 2019 in healthy adults: a randomized, double-blind, placebo-controlled, phase II trial.

BACKGROUND: Innovative coronavirus disease 2019 (COVID-19) vaccines, with elevated global manufacturing capacity, enhanced safety and efficacy, simplified dosing regimens, and distribution that is less cold chain-dependent, are still global imperatives for tackling the ongoing pandemic. A previous phase I trial indicated that the recombinant COVID-19 vaccine (V-01), which contains a fusion protein (IFN-PADRE-RBD-Fc dimer) as its antigen, is safe and well tolerated, capable of inducing rapid and robust immune responses, and warranted further testing in additional clinical trials. Herein, we aimed to assess the immunogenicity and safety of V-01, providing rationales of appropriate dose regimen for further efficacy study. METHODS: A randomized, double-blind, placebo-controlled phase II clinical trial was initiated at the Gaozhou Municipal Centre for Disease Control and Prevention (Guangdong, China) in March 2021. Both younger (n = 440; 18-59 years of age) and older (n = 440; ≥60 years of age) adult participants in this trial were sequentially recruited into two distinct groups: two-dose regimen group in which participants were randomized either to follow a 10 or 25 µg of V-01 or placebo given intramuscularly 21 days apart (allocation ratio, 3:3:1, n = 120, 120, 40 for each regimen, respectively), or one-dose regimen groups in which participants were randomized either to receive a single injection of 50 µg of V-01 or placebo (allocation ratio, 3:1, n = 120, 40, respectively). The primary immunogenicity endpoints were the geometric mean titers of neutralizing antibodies against live severe acute respiratory syndrome coronavirus 2, and specific binding antibodies to the receptor binding domain (RBD). The primary safety endpoint evaluation was the frequencies and percentages of overall adverse events (AEs) within 30 days after full immunization. RESULTS: V-01 provoked substantial immune responses in the two-dose group, achieving encouragingly high titers of neutralizing antibody and anti-RBD immunoglobulin, which peaked at day 35 (161.9 [95% confidence interval [CI]: 133.3-196.7] and 149.3 [95%CI: 123.9-179.9] in 10 and 25 µg V-01 group of younger adults, respectively; 111.6 [95%CI: 89.6-139.1] and 111.1 [95%CI: 89.2-138.4] in 10 and 25 µg V-01 group of older adults, respectively), and remained high at day 49 after a day-21 second dose; these levels significantly exceed those in convalescent serum from symptomatic COVID-19 patients (53.6, 95%CI: 31.3-91.7). Our preliminary data show that V-01 is safe and well tolerated, with reactogenicity predominantly being absent or mild in severity and only one vaccine-related grade 3 or worse AE being observed within 30 days. The older adult participants demonstrated a more favorable safety profile compared with those in the younger adult group: with AEs percentages of 19.2%, 25.8%, 17.5% in older adults vs. 34.2%, 23.3%, 26.7% in younger adults at the 10, 25 µg V-01 two-dose group, and 50 µg V-01 one-dose group, respectively. CONCLUSIONS: The vaccine candidate V-01 appears to be safe and immunogenic. The preliminary findings support the advancement of the two-dose, 10 µg V-01 regimen to a phase III trial for a large-scale population-based evaluation of safety and efficacy. TRIAL REGISTRATION: http://www.chictr.org.cn/index.aspx (No. ChiCTR2100045107, http://www.chictr.org.cn/showproj.aspx?proj=124702).

SARS-CoV-2-Triggered Mast Cell Rapid Degranulation Induces Alveolar Epithelial Inflammation and Lung Injury

SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. Here we showed that SARS-CoV-2-triggeed MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation alterred various signaling pathways in alveolar epithelial cells, particularly, led to the production of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/449680v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@899996org.highwire.dtl.DTLVardef@1c26c0eorg.highwire.dtl.DTLVardef@1442cdcorg.highwire.dtl.DTLVardef@dd4204_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefSARS-CoV-2 triggers an immediate mast cell (MC) degranulation, which initiates the alveolar epithelial inflammation and disrupts the tight junction. MC stabilizers that block degranulation reduce virus-induced lung inflammation and injury. HighlightsO_LIThe binding of RBD of Spike protein of SARS-CoV-2-to ACE2 receptor protein triggers an immediate MC degranulation C_LIO_LIMC degranulation induces transcriptomic changes include an upregulated inflammatory signaling and a downregulated cell-junction signaling C_LIO_LIMC degranulation leads to alveolar epithelial inflammation and disruption of tight junctions C_LIO_LIMC stabilizer that inhibits degranulation reduces SARS-CoV-2-induced lung inflammation and injury in vivo C_LI