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Membranes Jun 2024Bacterial extracellular vesicles (bEVs) secreted by Gram-negative bacteria are referred to as outer membrane vesicles (OMVs) because they originate in the outer...
Bacterial extracellular vesicles (bEVs) secreted by Gram-negative bacteria are referred to as outer membrane vesicles (OMVs) because they originate in the outer membrane. OMVs are membrane-coated vesicles 20-250 nm in size. They contain lipopolysaccharide (LPS), peptidoglycan, proteins, lipids, nucleic acids, and other substances derived from their parent bacteria and participate in the transmission of information to host cells. OMVs have broad prospects in terms of potential application in the fields of adjuvants, vaccines, and drug delivery vehicles. Currently, there remains a lack of efficient and convenient methods to isolate OMVs, which greatly limits OMV-related research. In this study, we developed a fast, convenient, and low-cost gradient filtration method to separate OMVs that can achieve industrial-scale production while maintaining the biological activity of the isolated OMVs. We compared the gradient filtration method with traditional ultracentrifugation to isolate OMVs from probiotic Nissle 1917 (EcN) bacteria. Then, we used RAW264.7 macrophages as an in vitro model to study the influence on the immune function of EcN-derived OMVs obtained through the gradient filtration method. Our results indicated that EcN-derived OMVs were efficiently isolated using our gradient filtration method. The level of OMV enrichment obtained via our gradient filtration method was about twice as efficient as that achieved through traditional ultracentrifugation. The EcN-derived OMVs enriched through the gradient filtration method were successfully taken up by RAW264.7 macrophages and induced them to secrete pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukins (ILs) 6 and 1β, as well as anti-inflammatory cytokine IL-10. Furthermore, EcN-derived OMVs induced more anti-inflammatory response (i.e., IL-10) than pro-inflammatory response (i.e., TNF-α, IL-6, and IL-1β). These results were consistent with those reported in the literature. The related literature reported that EcN-derived OMVs obtained through ultracentrifugation could induce stronger anti-inflammatory responses than pro-inflammatory responses in RAW264.7 macrophages. Our simple and novel separation method may therefore have promising prospects in terms of applications involving the study of OMVs.
PubMed: 38921502
DOI: 10.3390/membranes14060135 -
Gels (Basel, Switzerland) Jun 2024A combination of Poloxamer 407 (P407) and hydroxypropyl methylcellulose (HPMC) hydrosols is proposed as an in situ thermo-gelling vehicle for the nasal drug delivery of...
A combination of Poloxamer 407 (P407) and hydroxypropyl methylcellulose (HPMC) hydrosols is proposed as an in situ thermo-gelling vehicle for the nasal drug delivery of chlorhexidine-silver nanoparticles conjugates (SN-CX). Optimization of the formulation was carried out by applying varying ratios of P407 and HPMC in the presence and absence of SN-CX so that gelation would occur in the temperature range of the nasal cavity (30-34 °C). Mechanisms for the observed gelation phenomena were suggested based on viscosimetry, texture analysis, and dynamic light scattering. Tests were carried out for sprayability, washout time, in vitro drug release, ex vivo permeation, and antimicrobial activity. When applied separately, HPMC was found to lower the P407 gelation temperature (T), whereas SN-CX increased it. However, in the presence of HPMC, SN-CX interfered with the P407 micellar organization in a principally contrasting way while leading to an even further decrease in T. SN-CX-loaded nasal formulations composed of P407 16% and HPMC 0.1% demonstrated a desired gelation at 31.9 °C, good sprayability (52.95% coverage of the anterior nasal cavity), mucoadhesion for 70 min under simulated nasal clearance, expedient release and permeation, and preserved anti-infective activity against seasonal Influenza virus and beta-coronavirus, and other pathogens. Our findings suggest that the current development could be considered a potential formulation of a protective nasal spray against respiratory infections.
PubMed: 38920931
DOI: 10.3390/gels10060385 -
Gels (Basel, Switzerland) May 2024Manna, a well-known herbal drug has multiple traditional and pharmaceutical uses and the entire composition, sugar derivatives and polyphenols, gives rise to a very...
Manna, a well-known herbal drug has multiple traditional and pharmaceutical uses and the entire composition, sugar derivatives and polyphenols, gives rise to a very interesting bioactive complex with versatile therapeutic and benefic properties such as antioxidant and anti-inflammatory activities. The aim of this research was to investigate a manna extract loaded in a pectin hydrogel as a synergic vehicle to evaluate the potential use of the complex for cosmetic and dermatological applications. In particular, the study set out to disclose manna properties as a wound healing agent with antimicrobial and reparative activity on infected tissues. Moreover, considering the correlation between antioxidant activity and antiaging potential, the extract was investigated in regard to the anti-elastase activity and skin whitening potential. The total phenolic content of each extract was also determined and a safe profile by in vitro cytotoxicity studies was verified. The hydrogel complex, containing the manna extract and pectin as the gelling agent, exhibited suitable properties in terms of pH (from 5.50 to 6.80), rheological behavior and ability of preserving the antioxidant activity of the manna exudate (around 10%). All the peculiarities that make the pectin hydrogels ideal systems for skin disease, as wound dressings and for antiaging cosmetic formulations.
PubMed: 38920898
DOI: 10.3390/gels10060351 -
Neurology. Genetics Jun 2024Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy...
BACKGROUND AND OBJECTIVES
Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dy/dy) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy/dy) LAMA2-RD mouse model and the (Col6a1) COL6-RD mouse model demonstrated decreased apoptosis.
METHODS
A phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data.
RESULTS
Twenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study.
DISCUSSION
This study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence of omigapil in a dose-finding phase 1 study.
TRIAL REGISTRATION INFORMATION
Clinical Trials NCT01805024.
PubMed: 38915423
DOI: 10.1212/NXG.0000000000200148 -
Scientific Reports Jun 2024Caffeic acid phenethyl ester (CAPE) and its derivatives exhibit considerable effects against hepatocellular carcinoma (HCC), with unquestioned safety. Here we...
Caffeic acid phenethyl ester (CAPE) and its derivatives exhibit considerable effects against hepatocellular carcinoma (HCC), with unquestioned safety. Here we investigated CAPE derivative 1' (CAPE 1') monotherapy to HCC, compared with sorafenib. HCC Bel-7402 cells were treated with CAPE 1', the IC50 was detected using CCK-8 analysis, and acute toxicity testing (5 g/kg) was performed to evaluate safety. In vivo, tumor growth after CAPE 1' treatment was evaluated using an subcutaneous tumor xenograft model. Five groups were examined, with group 1 given vehicle solution, groups 2, 3, and 4 given CAPE 1' (20, 50, and 100 mg/kg/day, respectively), and group 5 given sorafenib (30 mg/kg/day). Tumor volume growth and tumor volume-to-weight ratio were calculated and statistically analyzed. An estimated IC50 was 5.6 µM. Acute toxicity tests revealed no animal death or visible adverse effects with dosage up to 5 g/kg. Compared to negative controls, CAPE 1' treatment led to significantly slower increases of tumor volume and tumor volume-to-weight. CAPE 1' and sorafenib exerted similar inhibitory effects on HCC tumors. CAPE 1' was non-inferior to sorafenib for HCC treatment, both in vitro and in vivo. It has great potential as a promising drug for HCC, based on effectiveness and safety profile.
Topics: Sorafenib; Caffeic Acids; Phenylethyl Alcohol; Carcinoma, Hepatocellular; Animals; Humans; Liver Neoplasms; Cell Line, Tumor; Mice; Xenograft Model Antitumor Assays; Antineoplastic Agents; Cell Proliferation; Mice, Nude; Mice, Inbred BALB C; Male
PubMed: 38914695
DOI: 10.1038/s41598-024-65496-1 -
Journal of Medicinal Chemistry Jun 2024Breast adenocarcinoma ranks high among the foremost lethal cancers affecting women globally, with its triple-negative subtype posing the greatest challenge due to its...
Breast adenocarcinoma ranks high among the foremost lethal cancers affecting women globally, with its triple-negative subtype posing the greatest challenge due to its aggressiveness and resistance to treatment. To enhance survivorship and patients' quality of life, exploring advanced therapeutic approaches beyond conventional chemotherapies is imperative. To address this, innovative nanoscale drug delivery systems have been developed, offering precise, localized, and stimuli-triggered release of anticancer agents. Here, we present perylenemonoimide nanoparticle-based vehicles engineered for deep-red light activation, enabling direct chlorambucil release. Synthesized via the reprecipitation technique, these nanoparticles were thoroughly characterized. Light-induced drug release was monitored via spectroscopic and reverse-phase HPLC. The efficacy of the said drug delivery system was evaluated in both two-dimensional and three-dimensional spheroidal cancer models, demonstrating significant tumor regression attributed to apoptotic cell death induced by efficient drug release within cells and spheroids. This approach holds promise for advancing targeted breast cancer therapy, enhancing treatment efficacy and minimizing adverse effects.
PubMed: 38913981
DOI: 10.1021/acs.jmedchem.4c00432 -
Archives of Microbiology Jun 2024The increase of multiple drug resistance bacteria significantly diminishes the effectiveness of antibiotic armory and subsequently exaggerates the level of therapeutic... (Review)
Review
The increase of multiple drug resistance bacteria significantly diminishes the effectiveness of antibiotic armory and subsequently exaggerates the level of therapeutic failure. Phytoconstituents are exceptional substitutes for resistance-modifying vehicles. The plants appear to be a deep well for the discovery of novel antibacterial compounds. This is owing to the numerous enticing characteristics of plants, they are easily accessible and inexpensive, extracts or chemicals derived from plants typically have significant levels of action against infections, and they rarely cause serious adverse effects. The enormous selection of phytochemicals offers very distinct chemical structures that may provide both novel mechanisms of antimicrobial activity and deliver us with different targets in the interior of the bacterial cell. They can directly affect bacteria or act together with the crucial events of pathogenicity, in this manner decreasing the aptitude of bacteria to create resistance. Abundant phytoconstituents demonstrate various mechanisms of action toward multi drug resistance bacteria. Overall, this comprehensive review will provide insights into the potential of phytoconstituents as alternative treatments for bacterial infections, particularly those caused by multi drug resistance strains. By examining the current state of research in this area, the review will shed light on potential future directions for the development of new antimicrobial therapies.
Topics: Anti-Bacterial Agents; Phytochemicals; Bacteria; Drug Resistance, Multiple, Bacterial; Bacterial Infections; Plant Extracts; Humans
PubMed: 38913205
DOI: 10.1007/s00203-024-04035-y -
International Journal of Pharmaceutics Jun 2024Wet bead milling (WBM) is one of the main approaches for manufacturing long acting injectable (LAI) suspensions, wherein the particle size of an Active Pharmaceutical...
Wet bead milling (WBM) is one of the main approaches for manufacturing long acting injectable (LAI) suspensions, wherein the particle size of an Active Pharmaceutical Ingredient (API) is reduced in a liquid vehicle via grinding. A common challenge observed during WBM is long milling time to achieve target particle size, resulting in poor milling efficiency. The objective of this work was to identify potential API attributes predictive of milling efficiency during WBM. In this study, physical and mechanical properties of nine APIs were characterized. Formulations with these APIs were manufactured using WBM. Bulk Young's Modulus was identified to have a significant influence on the rate of particle attrition. The rank order of Young's Moduli of the APIs was consistent with that of milling efficiency, estimated by an empirical function defined in this study called Milling Resistance (ϕ), representing the holistic impact of milling time, tip speed, bead loading, and batch to chamber volume ratio. The identification of such intrinsic material properties, which provide an early evaluation of potential manufacturing risks, is beneficial to product development, as these assessments can be performed with limited quantities of materials and help identify and design out scale-up challenges.
PubMed: 38909922
DOI: 10.1016/j.ijpharm.2024.124365 -
American Journal of Preventive Medicine Jun 2024People experiencing homelessness (PEH) are highly vulnerable to discrimination and violence, which impact physical and mental health. The study examines past-month...
INTRODUCTION
People experiencing homelessness (PEH) are highly vulnerable to discrimination and violence, which impact physical and mental health. The study examines past-month discrimination and violence against PEH in Los Angeles County (LAC).
METHODS
332 PEH in LAC were surveyed about their past-month experiences with discrimination, physical violence, and sexual violence from April-July 2023. Analyses were conducted in 2023.
RESULTS
31.8% of respondents reported experiencing discrimination daily and 53.9% reported it weekly, whereas rates of lifetime discrimination in studies of general populations of minoritized groups range between 13-60%. Nearly half of respondents who reported experiencing discrimination (49.6%) believed that their housing situation was the reason they were targeted. Victimization was also common, with 16.0% of participants experiencing physical violence and 7.5% experiencing sexual violence in the past 30 days. These rates of past-month victimization are high when compared to past-year physical violence (3.0%) and sexual violence (0.24%) among general populations in major U.S. cities. In multivariate regression analyses, discrimination was associated with being unsheltered in a vehicle (p<0.05) or outdoors (p<0.001), weekly illicit drug use (p<0.01), and psychological distress (p<0.001); violent victimization was associated with being sheltered (p<0.05) or unsheltered outdoors (p<0.001), physical health conditions (p<0.05), and psychological distress (p<0.01); and sexual victimization was associated with non-male gender (p<0.05) and being unsheltered outdoors (p<0.05). Discrimination and victimization outcomes were not associated with any race/ethnicity, sexual orientation, or time homeless characteristics.
CONCLUSIONS
Study findings highlight the dangers of homelessness in the U.S., particularly for those who are unsheltered outdoors.
PubMed: 38908722
DOI: 10.1016/j.amepre.2024.06.016 -
Lupus Science & Medicine Jun 2024Systemic lupus erythematosus (SLE) is a type of autoimmune disease that involves multiple organs involved as well as cytokine dysregulation. The treatment of SLE is...
OBJECTIVE
Systemic lupus erythematosus (SLE) is a type of autoimmune disease that involves multiple organs involved as well as cytokine dysregulation. The treatment of SLE is still challenging due to the side effects of the different drugs used. Receptor-interacting protein kinase 1 (RIPK1) is a kinase involved in T cell homeostasis and autoinflammation. Although clinical trials have shown that RIPK1 inhibition exhibits significant efficacy in different autoimmune diseases, its role in SLE remains unclear.
METHODS
MRL/lpr lupus-prone mice received RIPK1 inhibitor ZJU37 or vehicle intraperitoneally for 10 weeks. A BM12-induced chronic graft-versus-host-disease (cGVHD) lupus-like model was introduced in RIPK1 D138N mice or C57BL/6 mice. Nephritis, serum autoantibody levels, dysregulation of adaptive immune response and cytokines were compared in treated and untreated mice.
RESULTS
ZJU37 alleviated the clinical features of the MRL/lpr mice including nephritis and anti-dsDNA antibody production. In addition, ZJU37 treatment reduced the proportion of double-negative T cells in the spleen and the cytokines of TNFα, IFN-γ, IL-6, IL-17 and IL-1β in the serum. Moreover, RIPK1 D138N mice were able to prevent the cGVHD lupus-like model from SLE attack, manifesting as anti-dsDNA antibody production, the proliferation of germinal centre B cells, plasma cells, and T follicular helper cells as well as IgG and C3 deposits in kidneys.
CONCLUSION
RIPK1 inhibition has a protective effect in the mouse model of SLE and can potentially become a new therapeutic target for SLE in humans.
Topics: Animals; Lupus Erythematosus, Systemic; Mice, Inbred MRL lpr; Receptor-Interacting Protein Serine-Threonine Kinases; Mice; Mice, Inbred C57BL; Disease Models, Animal; Graft vs Host Disease; Cytokines; Female; Antibodies, Antinuclear; Lupus Nephritis; T-Lymphocytes; Spleen
PubMed: 38906550
DOI: 10.1136/lupus-2024-001146