The Pharmacogenetic Variability Associated With the Pharmacokinetics and Pharmacodynamics of Rivaroxaban in Healthy Chinese Subjects: A National Multicenter Exploratory Study.

PURPOSE: This study aimed to explore the pharmacogenetic variability associated with the pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in healthy Chinese subjects. METHODS: This was a multicenter study that included 304 healthy adults aged 18 to 45 years with unknown genotypes. All participants were administered a single dose of rivaroxaban at 10 mg, 15 mg, or 20 mg. PK and PD parameters were measured, and exome-wide association analysis was conducted. FINDINGS: Sixteen SNPs located on 11 genes influenced the AUC0-t. Among these, the 3 most influential genes were MiR516A2, PARP14, and MIR618. Thirty-six SNPs from 28 genes were associated with the PD of rivaroxaban. The 3 most influential genes were PKNOX2, BRD3, and APOL4 for anti-Xa activity, and GRIP2, PLCE1, and MLX for diluted prothrombin time (dPT). Among them, BRD3 played an important role in both the PK and PD of rivaroxaban. Anti-Xa activity (ng/mL) differed significantly among subjects with BRD3 rs467387: 145.1 ± 55.5 versus 139.9 ± 65.1 versus 164.0 ± 68.6 for GG, GA, and AA carriers, respectively (P = 0.0002). IMPLICATIONS: This study found that that the regulation of the BRD3 gene might affect the PK and PD of rivaroxaban, suggesting that it should be studied as a new pharmacologic target. The correlation between this gene locus and clinical outcomes has yet to be verified in patients undergoing clinical treatment.

Safety, tolerability, and pharmacokinetics of aildenafil citrate tablets, a novel oral PDE5 inhibitor, in healthy Chinese volunteers after multiple-dose administration.

Background: Aildenafil citrate is a potent and selective inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase type 5, developed for the treatment of erectile dysfunction (ED). Aim: This study aimed to assess the pharmacokinetics, safety, and tolerability of aildenafil citrate tablets after multiple doses in healthy Chinese males. Methods: Twenty participants were divided into 2 groups, 10 participants each. Participants were administered multiple doses of aildenafil citrate tablets at 30 and 60 mg. Outcomes: The safety evaluation was based on clinical symptoms and adverse events. Concentrations of aildenafil and its key metabolites (M1, M5, and M12) in human serum were measured by liquid chromatography-tandem mass spectrometry. Results: Pharmacokinetic analysis showed rapid absorption and elimination of aildenafil, with a median time to maximum serum concentration of 1 hour and mean terminal half-lives of 2.75 and 3.26 hours in the respective dose groups. The mean maximum concentration was proportional to the aildenafil dose in the range of 30 to 60 mg, although the area under the curve was not proportional for serum concentration vs time 0 to the last measurable time point (24 hours). Multiple doses of aildenafil were well tolerated, with 60.0% of men experiencing treatment-emergent adverse events, notably myalgia and fatigue, particularly in the 60-mg group. Clinical Implications: Aildenafil citrate tablets demonstrated favorable tolerability with once-daily administration over the clinical dose range. The occurrence of myalgia and fatigue was more prevalent in the 60-mg group. From a pharmacokinetic perspective, optimal administration of aildenafil citrate tablets appears to be 1 hour before sexual intercourse in men with ED. Strengths and Limitations: This study presents robust safety and pharmacokinetic data at expected therapeutic doses, unaffected by clinical factors. The efficacy of aildenafil citrate tablets warrants further validation in individuals with ED. Conclusion: Aildenafil citrate tablets exhibited good tolerability in healthy Chinese males following multiple doses at 30 and 60 mg. The 60-mg group showed an increased incidence of myalgia and fatigue, suggesting the need for heightened clinical vigilance. The mean maximum concentration, but not the area under the curve, displayed dose proportionality within the 30- to 60-mg dose range, and no significant drug accumulation was observed with repeated daily administration. Clinical Trial Registration: CTR20192473 (http://www.chinadrugtrials.org.cn).

C-type lectin-like receptor 2: roles and drug target.

C-type lectin-like receptor-2 (CLEC-2) is a member of the C-type lectin superfamily of cell surface receptors. The first confirmed endogenous and exogenous ligands of CLEC-2 are podoplanin and rhodocytin, respectively. CLEC-2 is expressed on the surface of platelets, which participates in platelet activation and aggregation by binding with its ligands. CLEC-2 and its ligands are involved in pathophysiological processes, such as atherosclerosis, cancer, inflammatory thrombus status, maintenance of vascular wall integrity, and cancer-related thrombosis. In the last 5 years, different anti- podoplanin antibody types have been developed for the treatment of cancers, such as glioblastoma and lung cancer. New tests and new diagnostics targeting CLEC-2 are also discussed. CLEC-2 mediates thrombosis in various pathological states, but CLEC-2-specific deletion does not affect normal hemostasis, which would provide a new therapeutic tool for many thromboembolic diseases. The CLEC-2-podoplanin interaction is a target for cancer treatment. CLEC-2 may be applied in clinical practice and play a therapeutic role.

IUPHAR ECR review: The cGAS-STING pathway: Novel functions beyond innate immune and emerging therapeutic opportunities.

Stimulator of interferon genes (STING) is a crucial innate immune sensor responsible for distinguishing pathogens and cytosolic DNA, mediating innate immune signaling pathways to defend the host. Recent studies have revealed additional regulatory functions of STING beyond its innate immune-related activities, including the regulation of cellular metabolism, DNA repair, cellular senescence, autophagy and various cell deaths. These findings highlight the broader implications of STING in cellular physiology beyond its role in innate immunity. Currently, approximately 10 STING agonists have entered the clinical stage. Unlike inhibitors, which have a maximum inhibition limit, agonists have the potential for infinite amplification. STING signaling is a complex process that requires precise regulation of STING to ensure balanced immune responses and prevent detrimental autoinflammation. Recent research on the structural mechanism of STING autoinhibition and its negative regulation by adaptor protein complex 1 (AP-1) provides valuable insights into its different effects under physiological and pathological conditions, offering a new perspective for developing immune regulatory drugs. Herein, we present a comprehensive overview of the regulatory functions and molecular mechanisms of STING beyond innate immune regulation, along with updated details of its structural mechanisms. We discuss the implications of these complex regulations in various diseases, emphasizing the importance and feasibility of targeting the immunity-dependent or immunity-independent functions of STING. Moreover, we highlight the current trend in drug development and key points for clinical research, basic research, and translational research related to STING.

A first-in-human study of Brozopentyl Sodium, following single and multiple ascending intravenous infusion in Chinese healthy volunteers.

BACKGROUND: Brozopentyl Sodium (BZP), a novel agent for ischemic stroke, has shown promising results in preclinical pharmacological studies, prompting the initiation of the first-in-human investigation. PURPOSE: This study aimed to assess the safety, tolerability, and pharmacokinetic (PK) characteristics of BZP in Chinese healthy volunteers. METHODS: The study consisted of two parts. Part I was a single-center, randomized, single-blinded, placebo-controlled, single-ascending study with six BZP dose cohorts (SAD: 25, 50, 100, 200, 300, and 400 mg). Part II was a single-center, randomized, single-blinded, placebo-controlled, multi-dose- and dose-elevated study with three BZP dose cohorts (MAD: 50, 100, and 200 mg). Doses were administered once daily on days 1 and 7 and twice daily on days 2-6. The PK properties of BZP and its bioactive metabolites, BNBP, were assessed. Safety and tolerability evaluations were also conducted. RESULTS: In the SAD study, BZP reached peak plasma concentrations (Tmax) at the end of administration, with median Tmax values ranging from 1 to 1.03 h, while BNBP reached Tmax between 1.25 to 1.38 h. The terminal half-lives (T1/2) were approximately 8 h for BZP and 15 h for BNBP. In the MAD study, steady-state plasma concentrations of BZP were reached by day 5. There was minimal accumulation of both BZP and BNBP after 7 days of administration. The area under the plasma concentration-time curve from 0 to time of the last measurable concentration (AUC0-t) and maximum plasma drug concentration (Cmax) showed dose-proportional increases for BZP but not for BNBP in both study parts. Single and multiple doses of BZP demonstrated a good safety profile and were well-tolerated. CONCLUSION: BZP displayed safety, good tolerability and predictable PK characteristics following both single and multiple ascending intravenous administrations. These findings provide a basis for further clinical development of BZP for ischemic stroke patients.

Optimal anti-platelet therapy for older patients with acute coronary syndrome: a network meta-analysis of randomized trials comprising 59,284 older patients.

The aim of this study was to identify the optimal anti-platelet therapy in older acute coronary syndrome (ACS) patients with a mean age ≥ 60 years by comparing the efficacy and safety of different anti-platelet therapies. The selection of antiplatelet therapy in older patients with ACS is a clinical challenge. Numerous evidences indicate that the de-escalation of dual anti-platelet therapy (DAPT) or P2Y12 inhibitor monotherapy may reduce bleeding risk without increasing thrombotic events. However, there is a lack of systematic reviews and optimal strategy analysis regarding older ACS patients. Randomized controlled trials (RCTs) of anti-platelet therapy in older ACS patients were identified. Major adverse cardiovascular events (MACE) were the primary outcome. Secondary outcomes included all death, cardiovascular death, myocardial infarction, stroke, stent thrombosis, and trial-defined major bleeding. Frequentist and Bayesian network meta-analyses were conducted. Treatments were ranked on posterior probability. Summary odds ratios (ORs) were estimated using Bayesian network meta-analysis. A total of 12 RCTs including 59,284 older ACS patients treated with five anti-platelet strategies were included. Ticagrelor monotherapy after 3 months DAPT was comparable to the other strategies (OR 0.73; 95% CI 0.32-1.6) in terms of MACE risk. Additionally, P score analysis and SUCRA Bayesian analysis showed that it was the most beneficial treatment for all deaths, cardiovascular death and revascularization. For safety, although there was no significant difference in direct comparisons, both SUCRA Bayesian (0.806) and P score (0.519) analysis suggested that ticagrelor monotherapy was the safest strategy. The current evidence demonstrated that ticagrelor monotherapy after 3 months DAPT may be a promising approach for achieving a more favorable balance between risk and benefit for older ACS patients, with a relatively low bleeding risk and without an increased risk of MACE events. Moreover, it remains the preferred option for clinical outcomes such as all death, CV death and revascularization. Further high-quality and long-term studies are required to validate anti-platelet therapies among older ACS patients.

De-escalation of Antiplatelet Therapy After Percutaneous Coronary Intervention in East Asian Patients With Acute Coronary Syndrome.

PURPOSE: East Asian individuals have a lower risk of thromboembolic events while potentially carrying a higher risk of bleeding events compared with non-Asian individuals. The aim of the present analysis was to investigate the effectiveness and safety of the de-escalation of antiplatelet therapy compared with standard dual antiplatelet therapy (DAPT) in East Asian patients undergoing percutaneous coronary intervention (PCI). METHODS: Randomized controlled trials comparing de-escalation with DAPT in patients with acute coronary syndrome (ACS) were retrieved from electronic databases from their inception until March 2022. Outcomes included major adverse cardiovascular events (MACE), ischemic events, major bleeding, minor bleeding, and any bleeding. Subgroup analyses based on treatment strategy were conducted. Statistical analysis was performed by using Review Manager version 5.4. FINDINGS: Eight randomized controlled trials from 539 potentially relevant publications with a total of 15,744 East Asian patients were included. Pooled data from these studies found a significantly lower MACE (0.82; 95% CI, 0.69-0.98) and major bleeding event (0.62; 95% CI, 0.46-0.82) in de-escalation than standard-DAPT without heterogeneity. Subgroup analysis was divided into DAPT followed by P2Y12 inhibitor monotherapy and a reducing dose of P2Y12 inhibitors. DAPT followed by P2Y12 inhibitor monotherapy had a 48% lower incidence of major bleeding events than standard DAPT (0.52; 95% CI, 0.27-1.00); there was no significant difference in major bleeding (0.99; 95% CI, 0.55-1.76) between the reducing dose of P2Y12 inhibitors and standard DAPT. IMPLICATIONS: De-escalation is a promising and potentially optimal antiplatelet therapy for patients from East Asia with PCI. DAPT followed by P2Y12 inhibitor monotherapy might be a safer and equally effective approach compared with standard DAPT in East Asian patients with PCI. PROSPERO identifier: CRD42022319983.

Intranasal mask for protecting the respiratory tract against viral aerosols.

The spread of many infectious diseases relies on aerosol transmission to the respiratory tract. Here we design an intranasal mask comprising a positively-charged thermosensitive hydrogel and cell-derived micro-sized vesicles with a specific viral receptor. We show that the positively charged hydrogel intercepts negatively charged viral aerosols, while the viral receptor on vesicles mediates the entrapment of viruses for inactivation. We demonstrate that when displaying matched viral receptors, the intranasal masks protect the nasal cavity and lung of mice from either severe acute respiratory syndrome coronavirus 2 or influenza A virus. With computerized tomography images of human nasal cavity, we further conduct computational fluid dynamics simulation and three-dimensional printing of an anatomically accurate human nasal cavity, which is connected to human lung organoids to generate a human respiratory tract model. Both simulative and experimental results support the suitability of intranasal masks in humans, as the likelihood of viral respiratory infections induced by different variant strains is dramatically reduced.

Urinary tract infections and genital mycotic infections associated with SGLT­2 inhibitors: an analysis of the FDA Adverse Event Reporting System.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a class of antihyperglycemic agents, including canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. Risk of urinary tract infections (UTIs) and genital mycotic infections (GMIs) associated with SGLT­2 inhibitors is of great clinical significance. The study aimed to assess the association between SGLT-2 inhibitors and occurrences of UTIs and GMIs using the FDA Adverse Event Reporting System (FAERS) database. METHODS: We used OpenVigil 2.1-MedDRA-v24 to query the FAERS database. Disproportionality analysis was performed to detect adverse event signals. Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) were calculated to measure the disproportionality. RESULTS: A total of 45,256 reports related to the use of SGLT-2 inhibitors, including 1,714 UTI cases and 438 GMI cases, were retrieved. Potential positive signals for UTIs and GMIs were identified for canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin in adult patients of all ages and both sexes. CONCLUSIONS: Data mining in the FAERS database suggests strong association between SGLT-2 inhibitors and UTIs/GMIs. These findings provide real-world evidence on the potential risk of UTIs/GMIs related to SGLT-2 inhibitors.

Platelet factor 4(PF4) and its multiple roles in diseases.

Platelet factor 4 (PF4) combines with heparin to form an antigen that could produce IgG antibodies and participate in heparin-induced thrombocytopenia (HIT). PF4 has attracted wide attention due to its role in novel coronavirus vaccine-19 (COVID-9)-induced immune thrombotic thrombocytopenia (VITT) and cognitive impairments. The electrostatic interaction between PF4 and negatively charged molecules is vital in the progression of VITT, which is similar to HIT. Emerging evidence suggests its multiple roles in hematopoietic and angiogenic inhibition, platelet coagulation interference, host inflammatory response promotion, vascular inhibition, and antitumor properties. The emerging pharmacological effects of PF4 may help deepen the exploration of its mechanism, thus accelerating the development of targeted therapies. However, due to its pleiotropic properties, the development of drugs targeting PF4 is at an early stage and faces many challenges. Herein, we discussed the characteristics and biological functions of PF4, summarized PF4-mediated signaling pathways, and discussed its multiple roles in diseases to inform novel approaches for successful clinical translational research.

Pharmacokinetic/LDL-C and exposure-response analysis of tafolecimab in Chinese hypercholesterolemia patients: Results from phase I, II, and III studies.

Tafolecimab, a novel fully human monoclonal antibody targeting PCSK9, has been assessed in Chinese healthy volunteers and patients with hypercholesterolemia. This analysis is to develop and qualify a population pharmacokinetics (PopPKs)/LDL-C model to characterize tafolecimab PK and LDL-C profiles, evaluate the impact of potential covariates on tafolecimab, estimate individual predicted exposure, and LDL-C decreasing, furthermore, explore exposure-response relationship to support clinical use. Data from six clinical trials in China were used to develop the PopPK/LDL-C model. A Michaelis-Menten approximation of the target-mediated drug disposition (TMDD) model was used to describe PK data and indirect response (IDR) model was developed to estimate the LDL-C profile. A stochastic approximation expectation maximization algorithm was applied to estimate PopPK/LDL-C parameters. The PK/LDL-C time course data for tafolecimab were well described by TMDD/IDR model. Baseline covariates resulting in statistically significant changes in PK/LDL-C parameters included: body weight and sex on absorption rate constant; body weight, sex, and unbound PCSK9 on central volume; body weight and sex on clearance; baseline LDL-C on first-order rate constants for the removal of an effect); and disease and sex on maximum effect. However, the magnitudes of changes associated with these covariates do not necessitate dose adjustment. Exposure-efficacy relationship indicated that the nadir of LDL-C reduction achieved with the steady-state trough plasma concentration (Ctrough ) of tafolecimab at 5 µg/mL, and no further LDL-C decreasing with the increasing Ctrough . There was no exposure dependency observed in exposure-safety exploration. The PopPK/LDL-C model was successfully developed, validated, and predicted tafolecimab/LDL-C concentrations and individual exposures.

Identification of immune-associated signatures and potential therapeutic targets for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) comprises a heterogeneous group of diseases with diverse aetiologies. It is characterized by increased pulmonary arterial pressure and right ventricular (RV) failure without specific drugs for treatment. Emerging evidence suggests that inflammation and autoimmune disorders are common features across all PAH phenotypes. This provides a novel idea to explore the characteristics of immunological disorders in PAH and identify immune-related genes or biomarkers for specific anti-remodelling regimens. In this study, we integrated three gene expression profiles and performed Gene Ontology (GO) and KEGG pathway analysis. CIBERSORT was utilized to estimate the abundance of tissue-infiltrating immune cells in PAH. The PPI network and machine learning were constructed to identify immune-related hub genes and then evaluate the relationship between hub genes and differential immune cells using ImmucellAI. Additionally, we implemented molecular docking to screen potential small-molecule compounds based on the obtained genes. Our findings demonstrated the density and distribution of infiltrating CD4 T cells in PAH and identified four immune-related genes (ROCK2, ATHL1, HSP90AA1 and ACTR2) as potential targets. We also listed 20 promising molecules, including TDI01953, pemetrexed acid and radotinib, for PAH treatment. These results provide a promising avenue for further research into immunological disorders in PAH and potential novel therapeutic targets.

Combined use of amlodipine and folic acid are significantly more efficacious than amlodipine alone in lowering plasma homocysteine and blood pressure among hypertensive patients with hyperhomocysteinemia and intolerance to ACEI: A multicenter, randomized, double-blind, parallel-controlled clinical trial.

Hyperhomocysteinemia with hypertension can synergistically increase the risk of stroke. The China stroke primary prevention trial showed that combining 0.8 mg folic acid (FA) with angiotensin-converting enzyme inhibitor (ACEI) can effectively lower plasma total homocysteine (tHcy) and blood pressure (BP); and reduce first stroke risk by additional 21% compared to ACEI alone. However, intolerance to ACEI is common in Asians and amlodipine can be alternative. This is a multicenter, randomized, double-blind, parallel-controlled clinical trial (RCT) which evaluated whether amlodipine combined with FA is more efficacious than amlodipine alone in lowering tHcy and BP among Chinese hypertensive with hyperhomocysteinemia and intolerance to ACEI. 351 Eligible patients were randomly assigned by 1:1:1 ratio to receive amlodipine-FA tablet daily (amlodipine 5 mg/FA 0.4 mg, A group); amlodipine 5 mg/FA 0.8 mg tablet daily (B group); amlodipine 5 mg daily (C group, control group). Follow-up was conducted at 2, 4, 6, and 8 weeks. The primary outcome was efficacy of lowering both tHcy and BP at the end of 8-week treatment. Compared with C group, A group had a significantly higher rate of lowering both tHcy and BP (23.3% vs. 6.0%; Odds Ratio [OR], 8.68; 95% CI, 3.04-24.78, P < .001); B group also had a higher rate of lowering both tHcy and BP (20.3% vs. 6.0%; OR: 5.90; 95% CI, 2.11-16.47, P < .001). This RCT showed amlodipine combined with FA compared with amlodipine alone, each had significantly higher efficacy of lowering both tHcy and BP. No difference was found in BP-lowering and occurrence of adverse events between the three groups.

The effects of pharmaceutical interventions on potentially inappropriate medications in older patients: a systematic review and meta-analysis.

Introduction: Potentially inappropriate medications (PIMs) is a particular concern in older patients and is associated with negative health outcomes. As various interventions have been developed to manage it, we performed a systematic review and meta-analysis to evaluate the effect of pharmaceutical interventions on outcomes of PIMs in older patients. Methods: Meta-analysis of eligible randomized controlled trials (RCTs) was conducted to report the outcomes of pharmaceutical interventions in older patients searching from the databases of Cochrane Library, PubMed, Embase, Web of Science, Clinicaltrials.gov, SinoMed and Chinese Clinical Trial Registry (ChiCTR). The PRISMA guidelines were followed and the protocol was registered in PROSPERO (CRD42019134754). Cochrane bias risk assessment tool and the modified Jadad scale were used to assess the risk bias. RevMan software was used for data processing, analysis and graphical plotting. Results: Sixty-five thousand, nine hundred seventy-one patients in 14 RCTs were included. Of the primary outcomes, pharmaceutical interventions could significantly reduce the incidence of PIMs in older patients (OR = 0.51, 95% CI: 0.42, 0.62; p < 0.001), and the number of PIMs per person (MD = -0.41, 95%CI: -0.51, -0.31; p < 0.001), accompanying by a low heterogeneity. Subgroup analysis showed that the application of computer-based clinical decision support for pharmacological interventions could remarkably decrease the incidence of PIMs and two assessment tools were more effective. Of the secondary outcomes, the meta-analysis showed that pharmacological interventions could reduce the number of drugs used per person (MD = -0.94, 95%CI: -1.51, -0.36; p = 0.001) and 30-day readmission rate (OR = 0.58, 95%CI: 0.36, 0.92; p = 0.02), accompanying by a low heterogeneity. However, the pharmaceutical interventions demonstrated no significant improvement on all-cause mortality and the number of falls. Conclusion: Our findings supported the efficacy of pharmaceutical interventions to optimize the use and management of drugs in older patients. Systematic review registration: https://clinicaltrials.gov/, CRD42019134754.

Identification of potential ferroptosis-associated biomarkers in rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation and gradual joint degeneration, resulting in function disability. Recently, ferroptosis, a novel form of regulated cell death that involves iron-dependent lipid peroxidation, has been implicated in the pathogenesis of RA. However, the underlying molecular mechanisms and key genes involved in ferroptosis in RA remain largely unknown. Methods: The GSE134420 and GSE77298 datasets were downloaded and DEGs were identified using R software. The DEGs were then mapped to the dataset of 619 ferroptosis-related genes obtained from the GeneCards database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to investigate the possible biological functions. Protein-protein interaction (PPI) networks were constructed to identify the hub genes. The relationship between hub genes and immune infiltration was estimated using the CIBERSORT algorithms. Gene Set Enrichment Analysis (GSEA) was used to explore the underlying signaling pathways of hub genes. Genome-wide association studies (GWAS) analysis was performed to confirm the pathogenic regions of the hub genes. RcisTarget and Gene-motif ranking databases were used to identify transcription factors (TFs) associated with the hub genes. The miRcode databases were utilized to construct the microRNA (miRNA)-messenger RNA (mRNA) network. Single-cell analysis was utilized to cluster cells and display the expression of hub genes in cell clusters. Finally, the expression and potential mechanism of hub genes were investigated in human and experimental samples. Results: Three hub genes PTGS2, ENO1, and GRN highly associated with ferroptosis were identified. Four pathogenic genes HLA-B, MIF, PSTPIP, TLR1 were identified that were significantly and positively correlated with the expression levels of hub genes. The results of the GSEA showed that the hub genes were significantly enriched in pathways related to immunity, lysosome, phagocytosis and infection. ENO1 and PTGS2 were enriched in the TF-binding motif of cisbp_M5493. The hub genes were validated in experimental and patient samples and highly level of ENO1 expression was found to inhibit ACO1, which reduces ferroptosis in proliferating fibroblast-like synoviocytes (FLS). Conclusion: PTGS2, ENO1 and GRN were identified and validated as potential ferroptosis-related biomarkers. Our work first revealed that ENO1 is highly expressed in RA synovium and that ferroptosis may be regulated by the ENO1-ACO1 axis, advancing the understanding of the underlying ferroptosis-related mechanisms of synovial proliferation and providing potential diagnostic and therapeutic targets for RA.

The Crosstalk between Nephropathy and Coagulation Disorder: Pathogenesis, Treatment, and Dilemmas.

ABSTRACT: The interaction between the kidney and the coagulation system greatly affects each other because of the abundant vessel distribution and blood perfusion in the kidney. Clinically, the risks of complicated thrombosis and bleeding have become important concerns in the treatment of nephropathies, especially nephrotic syndrome, CKD, ESKD, and patients with nephropathy undergoing RRTs. Adverse effects of anticoagulant or procoagulant therapies in patients with nephropathy, especially anticoagulation-related nephropathy, heparin-induced thrombocytopenia, and bleeding, seriously worsen the prognosis of patients, which have become challenges for clinicians. Over the decades, the interaction between the kidney and the coagulation system has been widely studied. However, the effects of the kidney on the coagulation system have not been systematically investigated. Although some coagulation-related proteins and signaling pathways have been shown to improve coagulation abnormalities while avoiding additional kidney damage in certain kidney diseases, their potential as anticoagulation targets in nephropathy requires further investigation. Here, we review the progression of research on the crosstalk between the coagulation system and kidney diseases and systematically analyze the significance and shortcomings of previous studies to provide new sight into future research. In addition, we highlight the status of clinical treatment for coagulation disorder and nephropathy caused by each other, indicating guidance for the formulation of therapeutic strategies or drug development.

Short-term antipsychotic treatment response in early-onset, typical-onset, and late-onset first episode schizophrenia.

In schizophrenia, the age at illness onset may reflect genetic loading and predict prognosis. We aimed to compare the pre-treatment symptom profiles and clinical symptom responses to antipsychotic treatment of individuals with late-onset schizophrenia (LOS; onset age: 40-59 years) with individuals with early-onset schizophrenia (EOS; onset age < 18 years) or typical-onset schizophrenia (TOS; onset age: 18-39 years). We conducted an 8-week cohort study in inpatient departments of five mental health hospitals in five cities in China. We included 106 individuals with LOS, 80 with EOS, and 214 with TOS. Their onset of schizophrenia was within three years and the disorders were minimally treated. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate clinical symptoms at baseline and after 8 weeks of antipsychotic treatment. Mixed effect models were used to compare symptom improvement within eight weeks. Antipsychotic therapy reduced all PANSS factor scores in all three groups. LOS had significantly better improvement in PANSS positive factor scores than EOS at week 8 after adjusting for sex, duration of illness, dose equivalents of antipsychotics at baseline, sites as fixed effects, and individuals as random effects. LOS was associated with reduced positive factor scores at week 8 when receiving 1 mg olanzapine dose equivalent per 1 kg body weight compared with EOS or TOS. In conclusion, LOS had better early improvement of positive symptoms than EOS and TOS. Thus, personalized treatment for schizophrenia should consider the age of onset.

A Phase 1 Multiple Dose Study of Tirzepatide in Chinese Patients with Type 2 Diabetes.

INTRODUCTION: To investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of tirzepatide in Chinese patients with type 2 diabetes (T2D). METHODS: In this phase 1, double-blind, placebo-controlled, multiple dose study, patients were randomized into one of two cohorts to receive once-weekly subcutaneous tirzepatide or placebo. The initial tirzepatide dose in both cohorts was 2.5 mg, which was increased by 2.5 mg every 4 weeks to a maximum final dose of 10.0 mg at week 16 (Cohort 1) or 15.0 mg at week 24 (Cohort 2). The primary outcome was the safety and tolerability of tirzepatide. RESULTS: Twenty-four patients were randomized (tirzepatide 2.5-10.0 mg: n = 10, tirzepatide 2.5-15.0 mg: n = 10, placebo: n = 4); 22 completed the study. The most frequently reported treatment-emergent adverse events (TEAEs) among patients receiving tirzepatide were diarrhea and decreased appetite; most TEAEs were mild and resolved spontaneously with no serious adverse events reported in the tirzepatide groups and one in the placebo group. The plasma concentration half-life of tirzepatide was approximately 5-6 days. Mean glycated hemoglobin (HbA1c) decreased over time from baseline in the 2.5-10.0 mg (- 2.4%) and 2.5-15.0 mg (- 1.6%) tirzepatide groups, at week 16 and week 24, respectively, but remained steady in patients receiving placebo. Body weight decreased from baseline by - 4.2 kg at week 16 in the tirzepatide 2.5-10.0 mg group and by - 6.7 kg at week 24 in the 2.5-15.0 mg group. Mean fasting plasma glucose levels fell from baseline by - 4.6 mmol/L in the tirzepatide 2.5-10.0 mg group at week 16 and by - 3.7 mmol/L at week 24 in the tirzepatide 2.5-15.0 mg group. CONCLUSIONS: Tirzepatide was well tolerated in this population of Chinese patients with T2D. The safety, tolerability, PK, and PD profile of tirzepatide support once-weekly dosing in this population. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT04235959.

The 3D Controllable Fabrication of Nanomaterials with FIB-SEM Synchronization Technology.

Nanomaterials with unique structures and functions have been widely used in the fields of microelectronics, biology, medicine, and aerospace, etc. With advantages of high resolution and multi functions (e.g., milling, deposition, and implantation), focused ion beam (FIB) technology has been widely developed due to urgent demands for the 3D fabrication of nanomaterials in recent years. In this paper, FIB technology is illustrated in detail, including ion optical systems, operating modes, and combining equipment with other systems. Together with the in situ and real-time monitoring of scanning electron microscopy (SEM) imaging, a FIB-SEM synchronization system achieved 3D controllable fabrication from conductive to semiconductive and insulative nanomaterials. The controllable FIB-SEM processing of conductive nanomaterials with a high precision is studied, especially for the FIB-induced deposition (FIBID) 3D nano-patterning and nano-origami. As for semiconductive nanomaterials, the realization of high resolution and controllability is focused on nano-origami and 3D milling with a high aspect ratio. The parameters of FIB-SEM and its working modes are analyzed and optimized to achieve the high aspect ratio fabrication and 3D reconstruction of insulative nanomaterials. Furthermore, the current challenges and future outlooks are prospected for the 3D controllable processing of flexible insulative materials with high resolution.