FZ-AD005, A Novel DLL3-Targeted Antibody-drug Conjugate with Topoisomerase I Inhibitor, Shows Potent Antitumor Activity in Preclinical Models.

Delta-like ligand 3 (DLL3) is overexpressed in small-cell lung cancer (SCLC) and has been considered an attractive target for SCLC therapy. Rovalpituzumab tesirine (Rova-T) was the first DLL3-targeted antibody-drug conjugate (ADC) to enter clinical studies. However, serious adverse events limited progress in the treatment of SCLC with Rova-T. In this study, we developed a novel DLL-3-targeted ADC, FZ-AD005, by using DXd with potent cytotoxicity and a relatively better safety profile to maximize the therapeutic index. FZ-AD005 was generated by a novel anti-DLL3 antibody FZ-A038 and a valine-alanine (Val-Ala) dipeptide linker to conjugate DXd. Moreover, Fc-silencing technology was introduced in FZ-AD005 to avoid off-target toxicity mediated by FcγRs and showed negligible Fc-mediated effector functions in vitro. In preclinical evaluation, FZ-AD005 exhibited DLL3-specific binding and demonstrated efficient internalization, bystander killing, and excellent in vivo antitumor activities in cell line-derived xenografts (CDX) and patient-derived xenograft (PDX) models. FZ-AD005 was stable in circulation with acceptable pharmacokinetic profiles in cynomolgus monkeys. FZ-AD005 was well tolerated in rats and monkeys. The safety profile of FZ-AD005 was favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys. In conclusion, FZ-AD005 has the potential to be a superior DLL3-targeted ADC with a wide therapeutic window and is expected to provide clinical benefits for the treatment of SCLC patients.

Acceptance and commitment therapy reduces psychological distress in patients with cancer: a systematic review and meta-analysis of randomized controlled trials.

Objective: This study aimed to systematically review and meta-analyze the clinical efficacy of acceptance and commitment therapy (ACT) in patients with cancer and psychological distress. Methods: Randomized controlled trials (RCTs) from seven English electronic databases were systematically investigated from inception to 3 October 2023. A total of 16 RCTs from 6 countries with 711 participants were included in this study. Estimated pooled effect sizes (ESs) were calculated via inverse-variance random-effects or fixed-effects (I2 ≤ 50%) model and presented by standardized mean difference (SMD). Subgroup analyses were performed to reduce confounding factors and heterogeneity, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to evaluate the quality of the pooled ESs. Results: The pooled ESs revealed that statistically significant improvements in anxiety [postintervention SMD = -0.41 (95% confidence interval (CI), -0.71, -0.11); p = 0.008; I2 = 65%; follow-up SMD = -0.37 (95% CI, -0.66, -0.08); p = 0.01; I2 = 29%], depression [postintervention SMD = -0.45 (95% CI, -0.63, -0.27); p < 0.001; I2 = 49%; follow-up SMD = -0.52 (95% CI, -0.77, -0.28); p < 0.001; I2 = 0%], and psychological flexibility [postintervention SMD = -0.81 (95% CI, -1.50, -0.11); p = 0.02; I2 = 84%; follow-up SMD = -0.71 (95% CI, -1.12, -0.31); p = 0.0006; I2 = 38%] in ACT-treated participants were observed compared to patients treated with control conditions. However, other outcomes, such as physical symptom alleviation, were not significantly associated. Conclusion: The findings of this systematic review and meta-analysis suggest that ACT is associated with improvements in anxiety, depression, and psychological flexibility in patients with cancer. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022320515.

Efficacy and Safety of Chaihu Jia Longgu Muli Decoction in the Treatment of Poststroke Depression: A Systematic Review and Meta-Analysis.

OBJECTIVE: Chaihu Jia Longgu Muli decoction (CLMD) is widely used in the treatment of poststroke depression (PSD) in China. Some evidences show that it has advantages, but there lacks reliable evidence. This study aims to systematically evaluate the efficacy and safety of CLMD in the treatment of PSD. METHODS: All randomized controlled trials (RCTs) of CLMD in the treatment of PSD were searched from the following databases: PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Database, and Chinese Biomedical Literature Service System (CBM), from their inception to May 2021. Two researchers independently screened the literature, extracted the data, and evaluated the risk of bias in the included studies. Meta-analysis was performed using RevMan5.3 software. RESULTS: A total of 13 RCTs involving 1665 patients were finally included in this study, among which 5 RCTs were oral CLMD alone versus antidepressants, and 8 RCTs were oral CLMD with antidepressants versus antidepressants. Meta-analysis results showed that oral administration of CLMD could improve Hamilton's Depression Scale (HAMD) and the Modified Edinburgh-Scandinavian Stroke Scale (MESSS) scores, improve the Barthel index, and have a low rate of adverse reactions, but there was no significant difference in the total effective rate (p=0.21 > 0.05) and the National Institute of Health Stroke Scale (NIHSS) score (p=0.47 > 0.05) between the antidepressants group and the oral administration of the CLMD group. Oral CLMD combined with antidepressants could improve the total effective rate, HAMD, and MESSS score, but there was no significant difference in Barthel index (p=0.06 > 0.05) and the adverse reaction rate (p=0.14 > 0.05) between the two groups. CONCLUSION: Current evidence suggests that oral CLMD alone or with antidepressants is more effective and safer in the treatment of PSD than oral antidepressants. Due to the limitation of the quality and quantity of the included studies, more high-quality studies are needed to confirm the above conclusion.

The Anti-Depressive Effects of Hesperidin and the Relative Mechanisms Based on the NLRP3 Inflammatory Signaling Pathway.

There is increasing evidence showing that inflammation is associated with depression in humans. Hesperidin, a natural bioflavonoid, has performed excellent effects on depression. The aim of this research was to investigate the therapeutic effect of hesperidin on chronic unpredictable mild stress (CUMS)-induced rats. The sucrose preference test (SPT), forced swimming test (FST), and open field test (OFT) were performed to measure the depression-related symptoms. The enzyme-linked immunosorbent assay (ELISA) was used to determine the concentrations of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α in the prefrontal cortex (PFC) of rats and cellular supernatant. PCR and Western blot were used to monitor the differences of NLRP3, caspase-1, ASC activation in the levels of genes and proteins in the PFC of rats and microglia. The activation of microglia was determined using immunofluorescence staining and flow cytometry assay. Our results show that hesperidin treatment significantly relieved depressive like behaviors in CUMS rats. In addition, hesperidin decreased the expression levels of IL-1ß, IL-6, TNF-α, NLRP3, caspase-1, and ASC in the PFC and microglia. This study investigated that hesperidin treatment ameliorated CUMS-induced depression by suppressing microglia and inflammation.

The efficacy and safety of acupuncture and moxibustion combined with western medicine for obsessive-compulsive disorder: A protocol for systematic review and meta-analysis.

BACKGROUND: Obsessive-compulsive disorder is common, chronic mental disorder, which is characterized by recurrent, unwanted, or intrusive thoughts and repetitive behaviors or mental action. Acupuncture and moxibustion, as a popular form of complementary and alternative therapy, have the advantages of low side effects, high safety, and low cost. The research showed that acupuncture and moxibustion have a good clinical efficacy on obsessive-compulsive disorder. However, there is no literature to systematically evaluate the efficacy and safety of acupuncture and moxibustion in treating obsessive-compulsive disorder. Thus, this study is aimed to evaluate the efficacy and safety of acupuncture and moxibustion for obsessive-compulsive disorder patients, providing reliable evidence for clinical application. METHODS: Randomized controlled trials of acupuncture and moxibustion combined with western medicine for the treatment of obsessive-compulsive disorder will be searched in the databases including PubMed, EMBASE, the Cochrane library, Web of science, China National Knowledge Infrastructure(CNKI), WanFang, the Chongqing VIP Chinese Science and Technology Periodical Database, and China biomedical literature database (CBM) from inception to June, 2020. In addition, Baidu, Google Scholar, International Clinical Trials Registry Platform, and Chinese Clinical Trials Registry will be searched to obtain the gray literature and relevant data that have not yet been published. Two qualified researchers will extract data and assess the risk of bias from included studies dependently. Statistical analysis is performed in RevMan 5.3 software. RESULTS: The efficacy and safety of acupuncture and moxibustion combined with western medicine for obsessive-compulsive disorder will be assessed based on the total effective rate, Hamilton Anxiety Scale score, Hamilton Rating Scale for Depression score, Clinical Global Impression score, side effects, and so on. CONCLUSIONS: The proposed systematic review and meta-analysis of acupuncture and moxibustion combined with western medicine for treating obsessive-compulsive disorder is expected to provide reliable evidence for clinical application. ETHICS AND DISSEMINATION: The private information from individuals will not publish. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/CDGTW.

Untargeted Metabolomic Analysis of the Effects and Mechanism of Nuciferine Treatment on Rats With Nonalcoholic Fatty Liver Disease.

Metabolomic analysis has been used to characterize the effects and mechanisms of drugs for nonalcoholic fatty liver disease (NAFLD) at the metabolic level. Nuciferine is an active component derived from folium nelumbinis and has been demonstrated to have beneficial effects on a high-fat diet (HFD) induced hepatic steatosis model. However, the effect of the altered metabolites of nuciferine on NAFLD has not yet been elucidated. In this study, we established a NAFLD rat model using HFD and treated with nuciferine. The lipid content levels, pro-inflammatory cytokines, and oxidative stress were investigated to access the therapeutic effects of nuciferine. Additionally, the metabolic regulatory mechanisms of nuciferine on NAFLD were analyzed using untargeted metabolomics. Gene expression of the key enzymes related to the changed metabolic pathways following nuciferine intervention was also investigated. The results showed that nuciferine treatment significantly reduced the body weight, levels of lipids, and liver enzymes in the blood and improved the hepatic steatosis in the NAFLD rat model. Nuciferine treatment also increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased the levels of methane dicarboxylic aldehyde (MDA) in the liver. Nuciferine treatment decreased the serum levels of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-alpha (TNF-α) and upregulated the gene expression of IL-6, IL-1ß, and TNF-α in the liver. Metabolomic analysis indicated a metabolism disorder in the NAFLD rat model reflected in a dysfunction of the glycerophospholipid, linoleic acid, alpha-linolenic acid, arginine and proline metabolism. Conversely, treatment with nuciferine improved the metabolic disorder in the NAFLD rat model. Nuciferine treatment also regulated the gene expression of key enzymes related to the glycerophospholipid, linoleic acid, and alpha-linolenic acid metabolism pathways in the liver. In conclusion, our study demonstrated an amelioration of the metabolic disorders following nuciferine treatment in NAFLD rat model. Our study contributes to the understanding of the effects and mechanisms of drugs for complex diseases using metabolomic analysis and experimental approaches.

Conjugation of DM1 to anti-CD30 antibody has potential antitumor activity in CD30-positive hematological malignancies with lower systemic toxicity.

An anti-CD30 antibody-drug conjugate incorporating the antimitotic agent DM1 and a stable SMCC linker, anti-CD30-MCC-DM1, was generated as a new antitumor drug candidate for CD30-positive hematological malignancies. Here, the in vitro and in vivo pharmacologic activities of anti-CD30-MCC-DM1 (also known as F0002-ADC) were evaluated and compared with ADCETRIS (brentuximab vedotin). Pharmacokinetics (PK) and the safety profiles in cynomolgus monkeys were assessed. Anti-CD30-MCC-DM1 was effective in in vitro cell death assays using CD30-positive lymphoma cell lines. We studied the properties of anti-CD30-MCC-DM1, including binding, internalization, drug release and actions. Unlike ADCETRIS, anti-CD30-MCC-DM1 did not cause a bystander effect in this study. In vivo, anti-CD30-MCC-DM1 was found to be capable of inducing tumor regression in subcutaneous inoculation of Karpas 299 (anaplastic large cell lymphoma), HH (cutaneous T-cell lymphoma) and L428 (Hodgkin's disease) cell models. The half-lives of 4 mg/kg and 12 mg/kg anti-CD30-MCC-DM1 were about 5 days in cynomolgus monkeys, and the tolerated dose was 30 mg/kg in non-human primates, supporting the tolerance of anti-CD30-MCC-DM1 in humans. These results suggest that anti-CD30-MCC-DM1 presents efficacy, safety and PK profiles that support its use as a valuable treatment for CD30-positive hematological malignancies.

Peptides derived from transcription factor EB bind to calcineurin at a similar region as the NFAT-type motif.

Calcineurin (CN) is involved in many physiological processes and interacts with multiple substrates. Most of the substrates contain similar motifs recognized by CN. Recent studies revealed a new CN substrate, transcription factor EB (TFEB), which is involved in autophagy. We showed that a 15-mer QSYLENPTSYHLQQS peptide from TFEB (TFEB-YLENP) bound to CN. When the TFEB-YLENP peptide was changed to YLAVP, its affinity for CN increased and it had stronger CN inhibitory activity. Molecular dynamics simulations revealed that the TFEB-YLENP peptide has the same docking sites in CN as the 15-mer DQYLAVPQHPYQWAK motif of the nuclear factor of activated T cells, cytoplasmic 1 (NFATc1-YLAVP). Moreover expression of the NFATc1-YLAVP peptide suppressed the TFEB activation in starved Hela cells. Our studies first identified a CN binding site in TFEB and compared the inhibitory capability of various peptides derived from CN substrates. The data uncovered a diversity in recognition sequences that underlies the CN signaling within the cell. Studies of CN-substrate interactions should lay the groundwork for developing selective CN peptide inhibitors that target CN-substrate interaction in vitro experiments.

Quercetin targets the interaction of calcineurin with LxVP-type motifs in immunosuppression.

Calcineurin (CN) is a unique calcium/calmodulin (CaM)-activated serine/threonine phosphatase. To perform its diverse biological functions, CN communicates with many substrates and other proteins. In the physiological activation of T cells, CN acts through transcriptional factors belonging to the NFAT family and other transcriptional effectors. The classic immunosuppressive drug cyclosporin A (CsA) can bind to cyclophilin (CyP) and compete with CN for the NFAT LxVP motif. CsA has debilitating side effects, including nephrotoxicity, hypertension and tremor. It is desirable to develop alternative immunosuppressive agents. To this end, we first tested the interactions between CN and the LxVP-type substrates, including endogenous regulators of calcineurin (RCAN1) and NFAT. Interestingly, we found that quercetin, the primary dietary flavonol, can inhibit the activity of CN and significantly disrupt the associations between CN and its LxVP-type substrates. We then validated the inhibitory effects of quercetin on the CN-NFAT interactions in cell-based assays. Further, quercetin also shows dose-dependent suppression of cytokine gene expression in mouse spleen cells. These data raise the possibility that the interactions of CN with its LxVP-type substrates are potential targets for immunosuppressive agents.