Effectiveness and safety of Arecae Semen compounds for patients with depression: a systematic review and meta-analysis.

BACKGROUND: Arecae Semen is a traditional herbal medicine widely used in the medical service and food industry, but in recent years, the carcinogenesis of edible Arecae Semen chewing has aroused comprehensive attention, therefore it is necessary to evaluate its medicinal properties. Increasing evidence has shown that Arecae Semen Compounds (ASC) possess antidepressant ability. This study aimed to evaluate the effectiveness and safety of ASC in the treatment of depression. METHODS: We retrieved articles in eight databases from their inception to May 2024. Randomized controlled trials (RCTs) comparing the effects of ASC alone or combined with routine treatment in patients with depression were identified. The Cochrane risk of bias (ROB) tool (ROB 2) was used for assessing the ROB in the included trials. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to assess the certainty of the evidence for the review outcomes. The outcomes included Hamilton depression rating scale (HAMD) scores, depression-related symptoms, serum dopamine levels, and adverse events. Stata 14.0 was used for data analysis calculating standardized mean difference (SMD) for continuous outcomes and relative risk (RR) for binary outcomes, both with 95% confidence intervals (CI). RESULTS: Nine RCTs involving 787 patients were included in this review. ASC lowered HAMD scores (SMD - 3.43, 95% CI - 5.24 to - 1.61; I2 = 95.2%, P < 0.001), alleviated depression-related symptoms, increased serum dopamine levels, and reduced the incidence of adverse events slightly (RR 0.18, 95% CI 0.04 to 0.77; I2 = 0, P = 0.775) compared with the control group. Publication bias might account for the asymmetrical presentation of funnel plots. Meta-regression analysis revealed that regarding HAMD scores, there was no significant relationship with duration, sample size, or treatment strategy. The evidence of the outcomes was of very low certainty. CONCLUSIONS: ASC may achieve better therapeutic effects, alleviate depression-related symptoms with a lower incidence of adverse events, and provide a potentially effective and safe complementary therapy for patients with depression. However, the evidence is very uncertain so further researches are required to validate our results and explore clinical implications of Arecae Semen in depth. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022361150.

Licoricesaponin G2 ameliorates bleomycin-induced pulmonary fibrosis via targeting TNF-α signaling pathway and inhibiting the epithelial-mesenchymal transition.

Background: Pulmonary fibrosis (PF) emerges as a significant pulmonary sequelae in the convalescent phase of coronavirus disease 2019 (COVID-19), with current strategies neither specifically preventive nor therapeutic. Licoricesaponin G2 (LG2) displays a spectrum of natural activities, including antibacterial, anti-inflammatory, and antioxidant properties, and has been effectively used in treating various respiratory conditions. However, the potential protective effects of LG2 against PF remain underexplored. Methods: Network analysis and molecular docking were conducted in combination to identify the core targets and pathways through which LG2 acts against PF. In the model of bleomycin (BLM)-induced C57 mice and transforming growth factor-ß1 (TGF-ß1)-induced A549 and MRC5 cells, techniques such as western blot (WB), quantitative Real-Time PCR (qPCR), Immunohistochemistry (IHC), Immunofluorescence (IF), and Transwell migration assays were utilized to analyze the expression of Epithelial-mesenchymal transition (EMT) and inflammation proteins. Based on the analysis above, we identified targets and potential mechanisms underlying LG2's effects against PF. Results: Network analysis has suggested that the mechanism by which LG2 combats PF may involve the TNF-α pathway. Molecular docking studies have demonstrated a high binding affinity of LG2 to TNF-α and MMP9. Observations from the study indicated that LG2 may mitigate PF by modulating EMT and extracellular matrix (ECM) remodeling. It is proposed that the therapeutic effect is likely arises from the inhibition of inflammatory expression through regulation of the TNF-α pathway. Conclusion: LG2 mitigates PF by suppressing TNF-α signaling pathway activation, modulating EMT, and remodeling the ECM. These results provide compelling evidence supporting the use of LG2 as a potential natural therapeutic agent for PF in clinical trials.

Performance Characterization and Composition Design Using Machine Learning and Optimal Technology for Slag-Desulfurization Gypsum-Based Alkali-Activated Materials.

Fly ash-slag-based alkali-activated materials have excellent mechanical performance and a low carbon footprint, and they have emerged as a promising alternative to Portland cement. Therefore, replacing traditional Portland cement with slag-desulfurization gypsum-based alkali-activated materials will help to make better use of the waste, protect the environment, and improve the materials' performance. In order to better understand it and thus better use it in engineering, it needs to be characterized for performance and compositional design. This study developed a novel framework for performance characterization and composition design by combining Categorical Gradient Boosting (CatBoost), simplicial homology global optimization (SHGO), and laboratory tests. The CatBoost characterization model was evaluated and discussed based on SHapley Additive exPlanations (SHAPs) and a partial dependence plot (PDP). Through the proposed framework, the optimal composition of the slag-desulfurization gypsum-based alkali-activated materials with the maximum flexural strength and compressive strength at 1, 3, and 7 days is Ca(OH)2: 3.1%, fly ash: 2.6%, DG: 0.53%, alkali: 4.3%, modulus: 1.18, and W/G: 0.49. Compared with the material composition obtained from the traditional experiment, the actual flexural strength and compressive strength at 1, 3, and 7 days increased by 26.67%, 6.45%, 9.64%, 41.89%, 9.77%, and 7.18%, respectively. In addition, the results of the optimal composition obtained by laboratory tests are very close to the predictions of the developed framework, which shows that CatBoost characterizes the performance well based on test data. The developed framework provides a reasonable, scientific, and helpful way to characterize the performance and determine the optimal composition for civil materials.

Factors related to the risk of stroke in the population with type 2 diabetes: A protocol for systematic review and meta-analysis.

BACKGROUND: Type 2 diabetes is an independent risk factor for stroke. The main role of the current study is to study the mechanism of stroke induced by diabetes, but there is no systematic summary of daily management and stroke prevention for patients with type 2 diabetes. In order to provide a more detailed stroke prevention program for patients with type 2 diabetes, we included in the study and looked forward to analyzing the risk factors that were more in line with the clinical characteristics of type 2 diabetes. METHODS: We will search the following Chinese and English databases: PubMed, Web of science, Cochrane Library, Medline, and China National Knowledge Infrastructure database. All of the above electronic databases will be searched from inception to June 30, 2021. In addition, we will manually search for conference papers, ongoing experiments, and internal reports to supplement the studies retrieved via electronic search. We will use the STATA 16.0 provided by Cochrane Collaboration Network for statistical analysis. RESULTS: The study will prove a collective view on the relationship between related factors and stroke in the type 2 diabetes population. CONCLUSION: We plan to submit this systematic review to a peer-reviewed journal.INPLASY registration number: INPLASY2021100046.

Prodrugs of PKC modulators show enhanced HIV latency reversal and an expanded therapeutic window.

AIDS is a pandemic disease caused by HIV that affects 37 million people worldwide. Current antiretroviral therapy slows disease progression but does not eliminate latently infected cells, which resupply active virus, thus necessitating lifelong treatment with associated compliance, cost, and chemoexposure issues. Latency-reversing agents (LRAs) activate these cells, allowing for their potential clearance, thus presenting a strategy to eradicate the infection. Protein kinase C (PKC) modulators-including prostratin, ingenol esters, bryostatin, and their analogs-are potent LRAs in various stages of development for several clinical indications. While LRAs are promising, a major challenge associated with their clinical use is sustaining therapeutically meaningful levels of the active agent while minimizing side effects. Here we describe a strategy to address this problem based on LRA prodrugs, designed for controllable release of the active LRA after a single injection. As intended, these prodrugs exhibit comparable or superior in vitro activity relative to the parent compounds. Selected compounds induced higher in vivo expression of CD69, an activation biomarker, and, by releasing free agent over time, significantly improved tolerability when compared to the parent LRAs. More generally, selected prodrugs of PKC modulators avoid the bolus toxicities of the parent drug and exhibit greater efficacy and expanded tolerability, thereby addressing a longstanding objective for many clinical applications.

Synthesis and Biological Evaluation of a Depsipeptidic Histone Deacetylase Inhibitor via a Generalizable Approach Using an Optimized Latent Thioester Solid-Phase Linker.

We describe the synthesis of Xyzidepsin, a depsipeptidic analogue of HDAC inhibitor Romidepsin (FK228), using a solid-phase strategy. Our latent thioester solid-phase linker was synthesized in 92% yield (three steps). Chemoselective conditions unmasked the thioester functionality and cyclized the depsipeptidic macrocycle. An IC50 value of 0.50 µM ± 0.05 was obtained for U937 cells. This synthetic route, well-suited to SAR, represents a generalizable route toward all manner of analogues, including structures with acidic and basic amino acids.

Synthesis and mechanistic investigations of pH-responsive cationic poly(aminoester)s.

The synthesis and degradation mechanisms of a class of pH-sensitive, rapidly degrading cationic poly(α-aminoester)s are described. These reactive, cationic polymers are stable at low pH in water, but undergo a fast and selective degradation at higher pH to liberate neutral diketopiperazines. Related materials incorporating oligo(α-amino ester)s have been shown to be effective gene delivery agents, as the charge-altering degradative behavior facilitates the delivery and release of mRNA and other nucleic acids in vitro and in vivo. Herein, we report detailed studies of the structural and environmental factors that lead to these rapid and selective degradation processes in aqueous buffers. At neutral pH, poly(α-aminoester)s derived from N-hydroxyethylglycine degrade selectively by a mechanism involving sequential 1,5- and 1,6-O→N acyl shifts to generate bis(N-hydroxyethyl) diketopiperazine. A family of structurally related cationic poly(aminoester)s was generated to study the structural influences on the degradation mechanism, product distribution, and pH dependence of the rate of degradation. The kinetics and mechanism of the pH-induced degradations were investigated by 1H NMR, model reactions, and kinetic simulations. These results indicate that polyesters bearing α-ammonium groups and appropriately positioned N-hydroxyethyl substituents are readily cleaved (by intramolecular attack) or hydrolyzed, representing dynamic "dual function" materials that are initially polycationic and transform with changing environment to neutral products.

Vancomycin-Arginine Conjugate Inhibits Growth of Carbapenem-Resistant E. coli and Targets Cell-Wall Synthesis.

The emergence of multi-drug-resistant Gram-negative bacteria, including carbapenem-resistant Enterobacteriaceae, is a major health problem that necessitates the development of new antibiotics. Vancomycin inhibits cell-wall synthesis in Gram-positive bacteria but is generally ineffective against Gram-negative bacteria and is unable to penetrate the outer membrane barrier. In an effort to determine whether vancomycin and other antibiotics effective against Gram-positive bacteria could, through modification, be rendered effective against Gram-negative bacteria, we discovered that the covalent attachment of a single arginine to vancomycin yielded conjugates with order-of-magnitude improvements in activity against Gram-negative bacteria, including pathogenic E. coli. The vancomycin-arginine conjugate (V-R) exhibited efficacy against actively growing bacteria, induced the loss of rod cellular morphology, and resulted in the intracellular accumulation of peptidoglycan precursors, all consistent with cell-wall synthesis disruption as its mechanism of action. Membrane permeabilization studies demonstrated an enhanced outer membrane permeability of V-R as compared with vancomycin. The conjugate exhibited no mammalian cell toxicity or hemolytic activity in MTT and hemolysis assays. Our study introduces a new vancomycin derivative effective against Gram-negative bacteria and underscores the broader potential of generating new antibiotics through combined mode-of-action and synthesis-informed design studies.

A Dual-Function Antibiotic-Transporter Conjugate Exhibits Superior Activity in Sterilizing MRSA Biofilms and Killing Persister Cells.

New strategies are urgently needed to target MRSA, a major global health problem and the leading cause of mortality from antibiotic-resistant infections in many countries. Here, we report a general approach to this problem exemplified by the design and synthesis of a vancomycin-d-octaarginine conjugate (V-r8) and investigation of its efficacy in addressing antibiotic-insensitive bacterial populations. V-r8 eradicated MRSA biofilm and persister cells in vitro, outperforming vancomycin by orders of magnitude. It also eliminated 97% of biofilm-associated MRSA in a murine wound infection model and displayed no acute dermal toxicity. This new dual-function conjugate displays enhanced cellular accumulation and membrane perturbation as compared to vancomycin. Based on its rapid and potent activity against biofilm and persister cells, V-r8 is a promising agent against clinical MRSA infections.

Vault Nanoparticles: Chemical Modifications for Imaging and Enhanced Delivery.

Vault nanoparticles represent promising vehicles for drug and probe delivery. Innately found within human cells, vaults are stable, biocompatible nanocapsules possessing an internal volume that can encapsulate hundreds to thousands of molecules. They can also be targeted. Unlike most nanoparticles, vaults are nonimmunogenic and monodispersed and can be rapidly produced in insect cells. Efforts to create vaults with modified properties have been, to date, almost entirely limited to recombinant bioengineering approaches. Here we report a systematic chemical study of covalent vault modifications, directed at tuning vault properties for research and clinical applications, such as imaging, targeted delivery, and enhanced cellular uptake. As supra-macromolecular structures, vaults contain thousands of derivatizable amino acid side chains. This study is focused on establishing the comparative selectivity and efficiency of chemically modifying vault lysine and cysteine residues, using Michael additions, nucleophilic substitutions, and disulfide exchange reactions. We also report a strategy that converts the more abundant vault lysine residues to readily functionalizable thiol terminated side chains through treatment with 2-iminothiolane (Traut's reagent). These studies provide a method to doubly modify vaults with cell penetrating peptides and imaging agents, allowing for in vitro studies on their enhanced uptake into cells.