A transient transcriptional activation governs unpolarized-to-polarized morphogenesis during embryo implantation.

During implantation, embryos undergo an unpolarized-to-polarized transition to initiate postimplantation morphogenesis. However, the underlying molecular mechanism is unknown. Here, we identify a transient transcriptional activation governing embryonic morphogenesis and pluripotency transition during implantation. In naive pluripotent embryonic stem cells (ESCs), which represent preimplantation embryos, we find that the microprocessor component DGCR8 can recognize stem-loop structures within nascent mRNAs to sequester transcriptional coactivator FLII to suppress transcription directly. When mESCs exit from naive pluripotency, the ERK/RSK/P70S6K pathway rapidly activates, leading to FLII phosphorylation and disruption of DGCR8/FLII interaction. Phosphorylated FLII can bind to transcription factor JUN, activating cell migration-related genes to establish poised pluripotency akin to implanting embryos. Resequestration of FLII by DGCR8 drives poised ESCs into formative pluripotency. In summary, we identify a DGCR8/FLII/JUN-mediated transient transcriptional activation mechanism. Disruption of this mechanism inhibits naive-poised-formative pluripotency transition and the corresponding unpolarized-to-polarized transition during embryo implantation, which are conserved in mice and humans.

Global miRNA dosage control of embryonic germ layer specification.

MicroRNAs (miRNAs) have essential functions during embryonic development, and their dysregulation causes cancer1,2. Altered global miRNA abundance is found in different tissues and tumours, which implies that precise control of miRNA dosage is important1,3,4, but the underlying mechanism(s) of this control remain unknown. The protein complex Microprocessor, which comprises one DROSHA and two DGCR8 proteins, is essential for miRNA biogenesis5-7. Here we identify a developmentally regulated miRNA dosage control mechanism that involves alternative transcription initiation (ATI) of DGCR8. ATI occurs downstream of a stem-loop in DGCR8 mRNA to bypass an autoregulatory feedback loop during mouse embryonic stem (mES) cell differentiation. Deletion of the stem-loop causes imbalanced DGCR8:DROSHA protein stoichiometry that drives irreversible Microprocessor aggregation, reduced primary miRNA processing, decreased mature miRNA abundance, and widespread de-repression of lipid metabolic mRNA targets. Although global miRNA dosage control is not essential for mES cells to exit from pluripotency, its dysregulation alters lipid metabolic pathways and interferes with embryonic development by disrupting germ layer specification in vitro and in vivo. This miRNA dosage control mechanism is conserved in humans. Our results identify a promoter switch that balances Microprocessor autoregulation and aggregation to precisely control global miRNA dosage and govern stem cell fate decisions during early embryonic development.

Molecular basis of differential receptor usage for naturally occurring CD55-binding and -nonbinding coxsackievirus B3 strains.

Receptor usage defines cell tropism and contributes to cell entry and infection. Coxsackievirus B (CVB) engages coxsackievirus and adenovirus receptor (CAR), and selectively utilizes the decay-accelerating factor (DAF; CD55) to infect cells. However, the differential receptor usage mechanism for CVB remains elusive. This study identified VP3-234 residues (234Q/N/V/D/E) as critical population selection determinants during CVB3 virus evolution, contributing to diverse binding affinities to CD55. Cryoelectron microscopy (cryo-EM) structures of CD55-binding/nonbinding isolates and their complexes with CD55 or CAR were obtained under both neutral and acidic conditions, and the molecular mechanism of VP3-234 residues determining CD55 affinity/specificity for naturally occurring CVB3 strains was elucidated. Structural and biochemical studies in vitro revealed the dynamic entry process of CVB3 and the function of the uncoating receptor CAR with different pH preferences. This work provides detailed insight into the molecular mechanism of CVB infection and contributes to an in-depth understanding of enterovirus attachment receptor usage.

Integrin-Linked Kinase in the Development of Gastric Tumors Induced by Helicobacter pylori: Regulation and Prevention Potential.

BACKGROUND: Integrin-linked kinase (ILK) is crucial in solid tumors by regulating the Hippo-Yes-associated protein 1 (YAP) pathway. This study aimed to uncover how Helicobacter pylori influences ILK levels and its role in regulating YAP during H. pylori-induced gastric cancer. MATERIALS AND METHODS: GES-1 cells with stable Ilk knockdown and overexpression and a mouse carcinogenesis model for H. pylori infection were constructed. And ILK, the phosphorylated mammalian STE20-like protein kinase 1 (MST1), large tumor suppressor 1 (LATS1; S909, T1079), and YAP (S109, S127) were detected in cells, and mice by western blotting, as well as fluorescence intensity of YAP were assayed by immunofluorescence. YAP downstream genes Igfbp4 and Ctgf, the pathological changes and tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1beta (IL-1ß), and nitric oxide (NO) levels in mice gastric tissues were detected by real-time PCR, H&E, and ELISA assays. RESULTS: In this study, stable Ilk knockdown cells exhibited significantly higher phosphorylated levels of MST1, LATS1, and YAP, as well as increased YAP in the nuclei of GES-1 cells. Conversely, cells with Ilk overexpression showed opposite results. H. pylori infection led to decreased ILK levels in gastric epithelial cells but increased ILK levels in gastric cancer cell lines (MGC803, SGC7901) and gastric cancer tissues in mice. Treatment with the ILK inhibitor OST-T315 elevated the phosphorylated MST, LATS1, and YAP levels, and inhibited the mRNA levels of Igfbp4 and Ctgf at 44, 48 week-aged mice. OST-T315 also reduced the release of TNF-α, IL-6, IL-1ß, and NO, as well as the progression of gastric cancer caused by H. pylori and N-Nitroso-N-methylurea (NMU) treatment. CONCLUSION: Upon initiation of gastric tumorigenesis signals, H. pylori increases ILK levels and suppresses Hippo signaling, thereby promoting YAP activation and gastric cancer progression. ILK can serve as a potential prevention target to impede H. pylori-induced gastric cancer.

Analysis of influencing factors on long COVID in COVID-19 patients infected with omicron variant three months after discharge: a cross-sectional study.

BACKGROUND: The purpose of this study is to analyze the influencing factors associated with Long-COVID in patients infected with Omicron variant of COVID-19 in Changchun City, Jilin Province, China three months after discharge in March 2022. METHODS: In this study, we conducted a telephone follow-up based on the real-world data collected from the Affiliated Hospital to Changchun University of Chinese Medicine, Changchun Tongyuan Shelter Hospital and Changchun Infectious Disease Hospital during the COVID-19 epidemic in Changchun in March 2022. We used the Global COVID-19 Clinical Platform Case Report Form for Post COVID condition as a follow-up questionnaire to collect the general information, past medical history, clinical symptoms, COVID-19 vaccine inoculation doses, and other relevant information to analyze the symptom characteristics of COVID-19 patients three months after discharge from the hospital and related factors affecting Long COVID. RESULTS: A total of 1,806 patients with COVID-19 were included in this study, 977 males and 829 females, with a mean age of 38.5 [30.0, 49.4] years, and the number of female patients suffering from Long COVID (50.87%) was greater than male patients (p = 0.023). The binary logistic regression analysis of factors influencing Long COVID showed that smoking history (OR (95%CI) = 0.551(0.425-0.714), p < 0.001, taking never smoking as a reference), allergy history (OR (95%CI) = 1.618 (1.086-2.413), p-value 0.018, taking no allergy as a reference), first symptoms (OR (95%CI) = 0.636 (0.501-0.807), p < 0.001, with no first symptoms as reference) and COVID-19 vaccine inoculation doses (OR (95%CI) = 1.517 (1.190-1.933), p-value 0.001, with ≤ 2 doses of COVID-19 vaccine inoculation doses as reference) constituted its influencing factors. The first symptoms of patients on admission mainly included fever (512 cases, 71.81%), cough (279 cases, 39.13%) and dry or itchy throat (211 cases, 29.59%). The most common symptoms of Long COVID were persistent fatigue (68 cases), amnesia (61 cases), insomnia (50 cases) and excessive sweating (50 cases). CONCLUSION: The first symptoms on admission were predominantly fever, cough and dry or itchy throat. The most common symptoms of Long COVID were persistent fatigue, amnesia, insomnia and excessive sweating, and female patients were at a higher risk of Long COVID.

Molecular basis of Coxsackievirus A10 entry using the two-in-one attachment and uncoating receptor KRM1.

KREMEN1 (KRM1) has been identified as a functional receptor for Coxsackievirus A10 (CV-A10), a causative agent of hand-foot-and-mouth disease (HFMD), which poses a great threat to infants globally. However, the underlying mechanisms for the viral entry process are not well understood. Here we determined the atomic structures of different forms of CV-A10 viral particles and its complex with KRM1 in both neutral and acidic conditions. These structures reveal that KRM1 selectively binds to the mature viral particle above the canyon of the viral protein 1 (VP1) subunit and contacts across two adjacent asymmetry units. The key residues for receptor binding are conserved among most KRM1-dependent enteroviruses, suggesting a uniform mechanism for receptor binding. Moreover, the binding of KRM1 induces the release of pocket factor, a process accelerated under acidic conditions. Further biochemical studies confirmed that receptor binding at acidic pH enabled CV-A10 virion uncoating in vitro. Taken together, these findings provide high-resolution snapshots of CV-A10 entry and identify KRM1 as a two-in-one receptor for enterovirus infection.

[Academic characteristics of contemporary famous traditional Chinese medicine experts and schools in treatment of chronic renal failure based on SrTO].

According to the systematic review of text and opinion(SrTO) developed by the Joanna Briggs Institute(JBI), this study integrated the evidence of the medical cases, papers, medical experience, and other related research of famous experts and schools on the treatment of chronic renal failure in the field of traditional Chinese medicine(TCM) nephropathy, analyzed the academic characteristics and influencing factors from the aspects of the principle, method, recipe, and medicines, and explored the internal logic and law of inheritance and innovation in TCM nephropathy. A total of 36 famous TCM experts and 4 schools were included. The work areas are concentrated in North and South China. 94.0% of the famous TCM experts have experienced master-disciple teaching. 27.8% have studied TCM through family succession. 38.9% have been taught by multiple famous teachers. And 5.6% have not experienced master-disciple teaching. In terms of principle, method, recipe, and medicines, many innovations have been made, with 30.6% of famous TCM experts proposing new theories, 11.1% advocating staged treatment of chronic renal failure, and 47.2% summarizing the treatment methods. The formation of the academic thoughts of contemporary famous TCM experts and schools on the treatment of chronic renal failure is closely related to the learning mode, era, and work area. Contemporary famous TCM experts and schools have the academic characteristics of combining classical and clinical theories and paying more attention to TCM with western medicine supplemented. The field of TCM nephropathy has the characteristics of simultaneous inheritance and innovation. On the basis of inheriting the classical theories of TCM, it absorbs modern medical theories, combines clinical diagnosis with the syndrome and treatment law of contemporary diseases, and makes innovations in principle, method, recipe, and medicines, which has significant clinical efficacy in the treatment of chronic renal failure.

Structures of human-infecting Thogotovirus fusogens support a common ancestor with insect baculovirus.

Thogotoviruses are emerging tick-borne zoonotic orthomyxoviruses infecting both humans and domestic animals with severe clinical consequences. These viruses utilize a single-envelope glycoprotein (Gp) to facilitate their entry into host cells. Here, we present the Gp structures of Thogoto and Dhori viruses, both of which are members of the Thogotovirus genus in the family Orthomyxoviridae These structures, determined in the postfusion conformation, identified them as class III viral fusion proteins. It is intriguing that the Gp structures are similar to the envelope protein of baculovirus, although sharing a low sequence identity of ∼28%. Detailed structural and phylogenic analyses demonstrated that these Gps originated from a common ancestor. Among the structures, domain I is the most conserved region, particularly the fusion loops. Domain II showed the highest variability among different viruses, which might be related to their distinct host tropism. These findings increase our understanding of the divergent evolution processes of various orthomyxoviruses and indicate potential targets for developing antiviral therapeutics by intercepting virus entry.

miRNA dosage control in development and human disease.

In mammals, miRNAs recognize target mRNAs via base pairing, which leads to a complex 'multiple-to-multiple' regulatory network. Previous studies have focused on the regulatory mechanisms and functions of individual miRNAs, but alterations of many individual miRNAs do not strongly disturb the miRNA regulatory network. Recent studies revealed the important roles of global miRNA dosage control events in physiological processes and pathogenesis, suggesting that miRNAs can be considered as a 'cellular buffer' that controls cell fate. Here, we review the current state of research on how global miRNA dosage is tightly controlled to regulate development, tumorigenesis, neurophysiology, and immunity. We propose that methods of controlling global miRNA dosage may serve as effective therapeutic tools to cure human diseases.

A retrospective analysis of the influencing factors of nucleic acid CT value fluctuation in COVID-19 patients infected with Omicron variant virus in Changchun city.

Objective: This study aimed to determine the risk factors associated with fluctuations in nucleic acid CT values in patients infected with the Omicron variant during an outbreak at a hospital in Changchun city. Methods: A retrospective analysis was conducted on general information, medical history, vaccination history, and laboratory test data of COVID-19 patients infected with the Omicron variant and admitted to the hospital in Changchun from March 2022 to April 2022. The study aimed to explore the factors influencing nucleic acid CT value fluctuations in COVID-19 patients infected with the Omicron variant in Changchun city. Results: Fluctuations in nucleic acid CT values were significantly correlated with occupation composition (p = 0.030), hospital stay duration (p = 0.000), heart rate (p = 0.026), creatinine (p = 0.011), platelet count (p = 0.000), glutamic-pyruvic transaminase (p = 0.045), and glutamic oxaloacetic transaminase (p = 0.017). Binary logistic regression analysis revealed significant correlations between hospital stay duration (p = 0.000), platelet count (p = 0.019), heart rate (p = 0.036), and nucleic acid CT value fluctuations (p < 0.05), indicating that they were independent risk factors. Red blood cell count was identified as a factor influencing nucleic acid CT value fluctuations in Group A patients. Occupation composition, direct bilirubin, and platelet count were identified as factors influencing nucleic acid CT value fluctuations in Group B patients. Further binary logistic regression analysis indicated that occupational composition and direct bilirubin are significant independent factors for nucleic acid CT value fluctuations in Group B patients, positively correlated with occupational risk and negatively correlated with direct bilirubin. Conclusion: Therefore, enhancing patients' immunity, increasing physical exercise to improve myocardial oxygen consumption, reducing the length of hospital stays, and closely monitoring liver function at the onset of hospitalization to prevent liver function abnormalities are effective measures to control fluctuations in nucleic acid CT values.

Coxsackievirus A10 impairs nail regeneration and induces onychomadesis by mimicking DKK1 to attenuate Wnt signaling.

Coxsackievirus A10 (CV-A10) infection, a prominent cause of childhood hand-foot-and-mouth disease (HFMD), frequently manifests with the intriguing phenomenon of onychomadesis, characterized by nail shedding. However, the underlying mechanism is elusive. Here, we found that CV-A10 infection in mice could suppress Wnt/ß-catenin signaling by restraining LDL receptor-related protein 6 (LRP6) phosphorylation and ß-catenin accumulation and lead to onychomadesis. Mechanistically, CV-A10 mimics Dickkopf-related protein 1 (DKK1) to interact with Kringle-containing transmembrane protein 1 (KRM1), the CV-A10 cellular receptor. We further found that Wnt agonist (GSK3ß inhibitor) CHIR99021 can restore nail stem cell differentiation and protect against nail shedding. These findings provide novel insights into the pathogenesis of CV-A10 and related viruses in onychomadesis and guide prognosis assessment and clinical treatment of the disease.

Pharmacokinetics and safety of a new generic lurasidone: a phase I bioequivalence study in healthy Chinese subjects.

Latuda® is a novel antipsychotic drug for schizophrenia and bipolar depression. A bioequivalence trial was performed to investigate the bioequivalence of Latuda® and its generic drug lurasidone. Two independent trials were carried out, each involving 28 subjects. In the fasting trial, subjects were randomly assigned to two groups (1:1 ratio), receiving either 40 mg of generic lurasidone or Latuda®. After a 7-day washout period, subjects entered the second period with a crossover administration of 40 mg of generic lurasidone or Latuda®. The postprandial study design was similar to that of the fasting study. In the fasting study, the pharmacokinetic (PK) parameter values of generic lurasidone and Latuda® were as follows: the Cmax was 28.84 ± 19.34 ng/ml and 28.22 ± 21.19 ng/ml, respectively; the AUC0-t was 121.39 ± 58.47 h*ng/ml and 118.35 ± 52.24 h*ng/ml, respectively; and the AUC0-∞ was 129.63 ± 63.26 h*ng/ml and 126.59 ± 57.99 h*ng/ml, respectively. The primary pharmacokinetic parameter, Cmax, was assessed for equivalence using reference-scaled average bioequivalence (RSABE), while other parameters (AUC0-t, AUC0-∞) were evaluated using average bioequivalence (ABE). The results indicate that both Cmax and AUC meet the equivalence criteria. In the postprandial study, the PK values of generic lurasidone and Latuda® were as follows: the Cmax was 74.89 ± 32.06 ng/ml and 83.51 ± 33.52 ng/ml, respectively; the AUC0-t was 274.77 ± 103.05 h*ng/ml and 289.26 ± 95.25 h*ng/ml, respectively; and the AUC0-∞ was 302.44 ± 121.60 h*ng/ml and 316.32 ± 109.04 h*ng/ml, respectively. The primary pharmacokinetic parameters (Cmax, AUC0-t, AUC0-∞) were assessed for equivalence using ABE, and both met the equivalence criteria. In the study, lurasidone and Latuda® both exhibited acceptable safety and tolerability. The results displayed that lurasidone and Latuda® were bioequivalent and safe in healthy Chinese participants. Clinical Trial Registry: This trial is registered at chinadrugtrials.org.cn (no.: CTR20191717, date: 2019.08.29).

Deciphering a reliable synergistic bispecific strategy of rescuing antibodies for SARS-CoV-2 escape variants, including BA.2.86, EG.5.1, and JN.1.

The game between therapeutic monoclonal antibodies (mAbs) and continuously emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has favored the virus, as most therapeutic mAbs have been evaded. Addressing this challenge, we systematically explored a reproducible bispecific antibody (bsAb)-dependent synergistic effect in this study. It could effectively restore the neutralizing activity of the bsAb when any of its single mAbs is escaped by variants. This synergy is primarily attributed to the binding angle of receptor-binding domain (RBD)-5, facilitating inter-spike cross-linking and promoting cryptic epitope exposure that classical antibody cocktails cannot achieve. Furthermore, RBD-5 with RBD-2, RBD-6, and RBD-7, alongside RBD-8, also exhibit significantly enhanced effects. This study not only shifts the paradigm in understanding antibody interactions but paves the way for developing more effective therapeutic antibodies against rapidly mutating SARS-CoV-2, with Dia-19 already showing promise against emerging variants like BA.2.86, EG.5.1, and JN.1.

Reporting Quality of Oral TCM Systematic Reviews Based on the PRISMA Harms Checklist from 2013 to 2020.

Background: Systematic reviews focusing on the effectiveness of different kinds of healthcare interventions have been widely published, but there were few guidelines for reporting safety concerns before 2016. The PRISMA harms checklist, which was published in 2016, can standardize reporting quality. Objectives: To evaluate the safety information reporting quality of oral traditional Chinese medicine (TCM) in systematic reviews before and after the PRISMA harms checklist was published and to explore factors associated with better reporting. Methods: We searched PubMed, the Cochrane Library, and Embase to identify all systematic reviews using oral TCM as interventions published before (from 2013 to 2015) and after (from 2017 to 2020) the PRISMA harms checklist was published. We used the PRISMA harms checklist to assess the quality of reporting of the safety information to included systematic reviews. Results: In total, 200 systematic reviews were sampled from eligible studies published between 2013 and 2020. Reviews from 2016 were excluded. Scores on the PRISMA harms checklist (23 items) ranged from 0 to 12. A systematic reviews published after 2016 had better reporting quality compared with studies published before 2016 with regard to the title (P=0.03), results of individual studies (P=0.016), and risk of bias across studies (P=0.043). In all included systematic reviews of our study, the state conclusion in coherence with review findings was reported adequately with the proportion of adherence at 95%; other items had a reporting proportion ranging from 0% to 57%. The four essential reporting items of the PRISMA harms checklist also had a low reporting quality ranging from 0% to 4%. Conclusions: Oral TCM systematic reviews reported inadequate safety information before and after the PRISMA harms checklist was published. This survey suggested that the PRISMA harms checklist should be recommended more to both original research and systematic review authors.

Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects.

BACKGROUND: Dasatinib (Sprycel®) is a tyrosine kinase inhibitor for treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. RESEARCH DESIGN & METHODS: We designed a clinical study to demonstrate that the dasatinib tablet (YiNiShu®) (Chia Tai Tianqing Pharmaceutical Group Co., Ltd) and Dasatinib (Bristol Myers Squibb) were bioequivalent under fasting and fed conditions. The whole study was structured into the fasting trial and the postprandial trial. Each period, subjects were given 50 mg dasatinib or its generic. The RSABE (reference scale average bioequivalence) and ABE (average bioequivalence) methods were employed to assess bioequivalence by pharmacokinetics (PK) parameters for a highly variable drug. RESULTS: 32 and 24 eligible volunteers were enrolled in the fasting and postprandial trials, respectively. In the fasting trial, the RSABE method was performed, and point estimates of Cmax, AUC0-t, and AUC0-∞ met the bioequivalence criteria. In the postprandial trial, the ABE method was performed, and the 90% CI of the geometric mean ratio (GMR) for PK parameters met the requirements of bioequivalence standards. CONCLUSION: The results proved that the PK parameters of the two drugs were similar and bioequivalent, indicating that both drugs had a good safety profile. CLINICAL TRIAL REGISTRATION: This trial was registered in ClinicalTrials.gov (Number: NCT05640804) and Drug Clinical Trial Registration and Information Disclosure Platform (Number: CTR20181708).

Comparing the bioequivalence and safety of liraglutide in healthy Chinese subjects: an open, single-dose, randomized, repeated, two-sequence, two-cycle phase I clinical trial.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) is an endogenous incretin hormone. Liraglutide, a GLP-1 receptor agonist, can lower blood sugar by increasing insulin production and inhibiting the production of glucagon. This study researched the bioequivalence and safety of the test and reference drugs in healthy Chinese subjects. RESEARCH DESIGN AND METHODS: Subjects (N = 28) were randomly divided into group A and group B at a ratio of 1:1 for a two-cycle cross-over study. There was single dose per cycle with subcutaneous injection of the test and reference drugs, respectively. The washout was set at 14 days. Plasma drug concentrations were detected by specific liquid chromatography and tandem mass spectrometry (LC-MS/MS) assays. Statistical analysis of major pharmacokinetic (PK) parameters was conducted to assess drug bioequivalence. In addition, we evaluated the safety of the drugs throughout the trial. RESULTS: The geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ for the test and reference drugs were 107.11%, 106.56%, 106.09%, respectively. The 90% confidence intervals (CIs) were all within 80%-125%, meeting the bioequivalence standards. In addition, both had good safety in this study. CONCLUSION: The study shows that the two drugs had similar bioequivalence and safety. CLINICAL TRIAL REGISTRATION: DCTR: CTR20190914; ClinicalTrials.gov: NCT05029076.

Corrigendum: Pharmacokinetics, Immunogenicity and Safety Study for SHR-1309 Injection and Perjeta® in Healthy Chinese Male Volunteers.

[This corrects the article DOI: 10.3389/fphar.2021.660541.].

Exploring the Potential Mechanism of Qi-Shen-Di-Huang Drug Formulary for Myasthenia Gravis (MG) based on UHPLC-QE-MS Network Pharmacology and Molecular Docking Techniques.

Myasthenia gravis (MG) is a rare and refractory autoimmune disease, and Qi Shen Di Huang (QSDH) drug formulary is an in-hospital herbal decoction with proven clinical efficacy in treating MG. Currently, most of the research on the QSDH drug formulary has concentrated on its clinical efficacy, and there is a lack of systematic study on the material basis. The active compounds and their mechanism of action have not been entirely determined. Therefore, this study sought to identify the active compounds in the QSDH drug formulary and analyze the key targets and potential mechanisms. We used ultra-performance liquid chromatography Q Exactive-mass spectrometry (UHPLC-QE-MS) and Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database to identify and screen 85 active ingredients corresponding to 59 potential targets (17 herbs) associated with myasthenia gravis, and further identified AKT1 as the primary core target and the PI3K/AKT signaling pathway as the most substantial enriched pathway. Molecular docking and UPLC-MS analysis identified quercetin, luteolin, wogonin, kaempferol, laccasein, and epigallocatechin gallate are the core compounds of the QSDH drug formulary. In vivo rat studies showed that the QSDH drug formulary reduced Lennon's clinical score and decreased acetylcholine receptor antibody levels in peripheral blood rats with experimental autoimmune myasthenia gravis. In addition, the QSDH drug formulary downregulated P-PI3K/PI3K and P-Akt/Akt protein expression. Collectively, these findings describe the role and potential mechanism of the QSDH drug formulary in the treatment of MG, which exerts potential value by acting on AKT targets and regulating the PI3K/AKT signaling pathway and providing a theoretical reference for QSDH drug formulary application in the clinical treatment of MG.

A randomized, double-blind, single-dose, single-center, parallel phase I clinical study comparing the pharmacokinetics, immunogenicity, safety, and tolerance of pertuzumab injection and Perjeta® in healthy Chinese male subjects.

BACKGROUND: Perjeta® is a recombinant, humanized monoclonal antibody that has been marketed and approved for the targeted therapy of human epidermal growth factor receptor (HER2) positive breast cancer in the United States. This study compared the bioequivalence, immunogenicity, and safety of pertuzumab injection (a biosimilar of Perjeta® produced by Chia Tai Tianqing Pharmaceutical Group Co., Ltd) and Perjeta® (produced by Roche Pharma AG) in healthy Chinese males. RESEARCH DESIGN AND METHODS: Healthy Chinese male subjects (N = 87) were randomly given intravenous injection of 5 mg/kg pertuzumab or Perjeta® at a 1:1 ratio. Plasma drug concentrations were detected by enzyme-linked immunosorbent assay, and primary pharmacokinetic parameters were statistically analyzed. We detected the levels of anti-drug antibody (ADA) and neutralizing antibody (nAb) to evaluate drug immunogenicity and safety of the drugs throughout the study. RESULTS: The geometric mean ratios of AUC0-t, Cmax, and AUC0-∞ for pertuzumab and Perjeta® were 100.42%, 96.71%, and 101.47%, respectively. The 90% CIs were all within 80%-125%, meeting the bioequivalence standards. The levels of ADA and nAb were similar. In addition, both had good safety in the study. CONCLUSION: The study shows that pertuzumab injection and Perjeta® had similar bioequivalence, immunogenicity, and safety.

Comparative the efficacy and acceptability of immunosuppressive agents for myasthenia gravis: A protocol for systematic review and network meta-analysis.

BACKGROUND: Immunosuppressive drugs are routinely used to treat myasthenia gravis (MG). However, current recommendations provide limited evidence to support treatment options, leading to considerable variation in practice among healthcare specialists. Hence, we present a protocol for a systematic review and network meta-analysis (NMA) to update the evidence by comparing the efficacy and acceptability of oral immunosuppressive drugs for the treatment of MG. METHODS: We will conduct a systematic review and NMA of all randomized controlled trials evaluating the following oral immunosuppressive drugs for the treatment of MG. Published studies will be searched using the following databases from inception to November 23, 2021: CENTRAL, the CINAHL, MEDLINE, Embase, PsycINFO, Web of Science, and 3 Chinese databases (Chinese Biomedical Literatures Database, CNKI, and Wan Fang database). Assessment of study eligibility and data extraction will be conducted independently by 2 reviewers. The main outcome will be a quantitative MG scoring system. We will conduct Bayesian NMA to synthesize all evidence for each outcome and obtain a comprehensive ranking of all treatments. The quality of the evidence will be evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations framework. RESULTS: The objective of this study was to assess the relative clinical efficacy and acceptability of first-line immunosuppressants for the treatment of MG, using a systematic review and NMA approach. CONCLUSION: In the absence of head-to-head trials comparing therapies, evidence from this NMA of available clinical trials will inform clinicians, patients, and families the risk-benefit profiles of different treatment options.