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Acta Pharmaceutica Sinica. B Jun 2024Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments. Lipase inhibitors hold therapeutic...
Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments. Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood‒tumor barrier (BTB). BTB activates its Wnt signaling to maintain barrier properties, , Mfsd2a-mediated BTB low transcytosis. Here, we reported VCAM-1-targeting nano-wogonin (W@V-NPs) as an adjuvant of nano-orlistat (O@V-NPs) to intensify drug delivery and inhibit lipogenesis of brain metastases. W@V-NPs were proven to be able to inactivate BTB Wnt signaling, downregulate BTB Mfsd2a, accelerate BTB vesicular transport, and enhance tumor accumulation of O@V-NPs. With the ability to specifically kill cancer cells in a lipid-deprived environment with IC at 48 ng/mL, W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice. The combination did not induce brain edema, cognitive impairment, and systemic toxicity in healthy mice. Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.
PubMed: 38828148
DOI: 10.1016/j.apsb.2024.03.024 -
Journal of Nanobiotechnology Jun 2024Research into mRNA vaccines is advancing rapidly, with proven efficacy against coronavirus disease 2019 and promising therapeutic potential against a variety of solid... (Review)
Review
Research into mRNA vaccines is advancing rapidly, with proven efficacy against coronavirus disease 2019 and promising therapeutic potential against a variety of solid tumors. Adjuvants, critical components of mRNA vaccines, significantly enhance vaccine effectiveness and are integral to numerous mRNA vaccine formulations. However, the development and selection of adjuvant platforms are still in their nascent stages, and the mechanisms of many adjuvants remain poorly understood. Additionally, the immunostimulatory capabilities of certain novel drug delivery systems (DDS) challenge the traditional definition of adjuvants, suggesting that a revision of this concept is necessary. This review offers a comprehensive exploration of the mechanisms and applications of adjuvants and self-adjuvant DDS. It thoroughly addresses existing issues mentioned above and details three main challenges of immune-related adverse event, unclear mechanisms, and unsatisfactory outcomes in old age group in the design and practical application of cancer mRNA vaccine adjuvants. Ultimately, this review proposes three optimization strategies which consists of exploring the mechanisms of adjuvant, optimizing DDS, and improving route of administration to improve effectiveness and application of adjuvants and self-adjuvant DDS.
Topics: Humans; Cancer Vaccines; Adjuvants, Immunologic; mRNA Vaccines; Nanotechnology; Neoplasms; Animals; Drug Delivery Systems; COVID-19; Adjuvants, Vaccine; RNA, Messenger; SARS-CoV-2; Vaccines, Synthetic
PubMed: 38825711
DOI: 10.1186/s12951-024-02590-6 -
Biomedicine & Pharmacotherapy =... Jul 2024Globally, infections due to multi-drug resistant (MDR) Gram-negative bacterial (GNB) pathogens are on the rise, negatively impacting morbidity and mortality,...
Globally, infections due to multi-drug resistant (MDR) Gram-negative bacterial (GNB) pathogens are on the rise, negatively impacting morbidity and mortality, necessitating urgent treatment alternatives. Herein, we report a detailed bio-evaluation of an ultrashort, cationic lipopeptide 'SVAP9I' that demonstrated potent antibiotic activity and acted as an adjuvant to potentiate existing antibiotic classes towards GNBs. Newly synthesized lipopeptides were screened against ESKAPE pathogens and cytotoxicity assays were performed to evaluate the selectivity index (SI). SVAP9I exhibited broad-spectrum antibacterial activity against critical MDR-GNB pathogens including members of Enterobacteriaceae (MIC 4-8 mg/L), with a favorable CC value of ≥100 mg/L and no detectable resistance even after 50th serial passage. It demonstrated fast concentration-dependent bactericidal action as determined via time-kill analysis and also retained full potency against polymyxin B-resistant E. coli, indicating distinct mode of action. SVAP9I targeted E. coli's outer and inner membranes by binding to LPS and phospholipids such as cardiolipin and phosphatidylglycerol. Membrane damage resulted in ROS generation, depleted intracellular ATP concentration and a concomitant increase in extracellular ATP. Checkerboard assays showed SVAP9I's synergism with narrow-spectrum antibiotics like vancomycin, fusidic acid and rifampicin, potentiating their efficacy against MDR-GNB pathogens, including carbapenem-resistant Acinetobacter baumannii (CRAB), a WHO critical priority pathogen. In a murine neutropenic thigh infection model, SVAP9I and rifampicin synergized to express excellent antibacterial efficacy against MDR-CRAB outcompeting polymyxin B. Taken together, SVAP9I's distinct membrane-targeting broad-spectrum action, lack of resistance and strong in vitro andin vivopotency in synergism with narrow spectrum antibiotics like rifampicin suggests its potential as a novel antibiotic adjuvant for the treatment of serious MDR-GNB infections.
Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Microbial Sensitivity Tests; Mice; Lipopeptides; Cell Membrane; Gram-Negative Bacterial Infections; Drug Synergism; Female; Humans; Adjuvants, Pharmaceutic
PubMed: 38823276
DOI: 10.1016/j.biopha.2024.116810 -
Spectrochimica Acta. Part A, Molecular... Oct 2024Letrozole is an anticancer medication prescribed for the management of estrogen receptor-positive breast cancer in postmenopausal women. Chronic pain is prevalent in...
A highly sensitive first derivative synchronous spectrofluorimetric approach for the simultaneous analysis of the anti-breast cancer co-administered drugs, letrozole and tramadol in dosage forms and human plasma at nanogram levels.
Letrozole is an anticancer medication prescribed for the management of estrogen receptor-positive breast cancer in postmenopausal women. Chronic pain is prevalent in patients receiving chemotherapy, leading to the use of adjuvant analgesics such as tramadol. This work introduces the first analytical approach for the concurrent quantification of letrozole and tramadol, two co-administered drugs, employing a rapid, highly sensitive, eco-friendly, and cost-effective first derivative synchronous spectrofluorimetric technique. The fluorescence of tramadol and letrozole was measured at wavelengths of 235.9 nm and 241.9 nm, respectively using a wavelength difference (Δλ) of 60.0 nm. The developed approach demonstrated exceptional linearity (r ˃ 0.999) within the specified concentration ranges for tramadol (10.0-1200.0 ng/mL) and letrozole (1.0-140.0 ng/mL). The results demonstrated that the proposed technique exhibits a high level of sensitivity, with detection limits of 0.569 and 0.143 ng/mL for tramadol and letrozole, respectively, indicating the good bioanalytical applicability. The within-run precisions, both intra-day and inter-day, for both analytes, were less than 0.71 % RSD. The developed approach was effectively applied to simultaneously estimate the mentioned drugs in their tablets and human plasma samples, achieving high percentage recoveries and low % RSD values. In order to assess the environmental sustainability of the developed approach, Analytical GREEnnessNNESS (AGREE) and the Green Analytical Procedure Index (GAPI) metric tools were employed. Both tools revealed that the developed approach is excellent green, suggesting its usage as an environmentally-friendly alternative for the routine assayof the investigated pharmaceuticals. The developed approach was validated according to the ICHQ2 (R1) requirements.
Topics: Letrozole; Tramadol; Humans; Spectrometry, Fluorescence; Breast Neoplasms; Female; Limit of Detection; Antineoplastic Agents; Reproducibility of Results; Tablets
PubMed: 38820815
DOI: 10.1016/j.saa.2024.124532 -
Paediatric Anaesthesia May 2024Pediatric hypnosis is an extremely valuable adjuvant therapeutic tool to reduce pain and ameliorate anxiety in children undergoing procedures and pediatric anesthesia....
Pediatric hypnosis is an extremely valuable adjuvant therapeutic tool to reduce pain and ameliorate anxiety in children undergoing procedures and pediatric anesthesia. This perspective summarises; why Integrating hypnosis into practice has this potential, some techniques that are particularly useful in this setting, the training oppurtunities to learn more, and recommendations for future pediatric anesthesia hypnotic research. There is definite capacity for change by Integrating hypnosis into our practice. Not only will this ensure more capable, confident children who present for peri-operative care but also reduce costs and the environmental impact of the pharmaceutical agents we currently employ for sedation and anxiolysis.
PubMed: 38812464
DOI: 10.1111/pan.14942 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Apr 2024Panax ginseng, known as the "king of herbs", is a highly valued medicinal plant, and its medicinal parts include roots, stems, leaves, flowers, and fruits,... (Review)
Review
Panax ginseng, known as the "king of herbs", is a highly valued medicinal plant, and its medicinal parts include roots, stems, leaves, flowers, and fruits, among which the roots are the most commonly used. The main active components of this medicinal plant include triterpenoid saponins, polysaccharides, peptides, and volatile oils. The chemical components and active metabolites endow this herb with a variety of pharmacological effects, and thus this herb is used to treat various diseases and play healthcare roles. Currently, a wide range of preparations of P. ginseng have been officially registered and marketed, including tablets, oral liquids, and injections, which demonstrate good clinical efficacy in regulating immunity, adjuvant treatment of tumors, alleviating fatigue, delaying the aging process, improving glucose and lipid metabolism, treating cardiovascular diseases, and relieving inflammation and pain. The production process and quality standards of these drugs are of great significance to ensure their efficacy. According to the theory that Ginseng Radix et Rhizoma can greatly replenish original Qi, tonify the spleen and lung, promote fluid production to quench thirst, tranquilize mind and enrich the intelligence, this paper systematically summarized the clinical application progress of P. ginseng and rela-ted preparations on the market and prospected the further development of preparations from P. ginseng, providing a reference for further exploring the medicinal value and healthcare function of this herb. The above contents, as an important basis for the in-depth development of P. ginseng and related drugs, increase the possibilities for the application of P. ginseng.
Topics: Panax; Humans; Drugs, Chinese Herbal; Animals
PubMed: 38812184
DOI: 10.19540/j.cnki.cjcmm.20231124.301 -
Thoracic Cancer May 2024To elucidate the treatment and surgery outcomes with or without perioperative therapies in Japanese patients with clinical stage III non-small cell lung cancer (NSCLC)...
Treatment patterns and clinical outcomes of resectable clinical stage III non-small cell lung cancer in a Japanese real-world setting: Surgery cohort analysis of the SOLUTION study.
BACKGROUND
To elucidate the treatment and surgery outcomes with or without perioperative therapies in Japanese patients with clinical stage III non-small cell lung cancer (NSCLC) in real-world settings.
METHODS
We performed subset analyses of the SOLUTION study, a multicenter, noninterventional, observational study of Japanese patients diagnosed with clinical stage III NSCLC, for those who started first-line treatment (surgery±perioperative therapy) between January 2013 and December 2014 (study registration: UMIN000031385). Follow-up data were obtained using medical records from diagnosis to March 1, 2018.
RESULTS
Of 149 eligible patients, 67 underwent surgery alone (median age 71 years) and 82 underwent surgery+perioperative therapy (median age 63 years). Lung resection was performed in 137 patients and the others underwent exploratory thoracotomy or other procedures. Perioperative therapies included adjuvant therapy only (n = 41), neoadjuvant therapy only (n = 24), and neoadjuvant+adjuvant therapy (n = 17). The median overall survival (OS) and 3-year OS rate were 29.3 months and 44.0%, respectively, in patients who underwent surgery alone, and not reached and 61.1%, respectively, in patients who underwent surgery+perioperative therapy. The 3-year progression-free survival (PFS) and disease-free survival (DFS) rates were 42.4% and 47.1%, respectively, in patients who underwent surgery+perioperative therapy and 28.5% and 28.9%, respectively, in patients who underwent surgery alone. In multivariable Cox regression, perioperative therapy was associated with improved OS (hazard ratio [95% confidence interval] 0.49 [0.29-0.81]), PFS (0.62 [0.39-0.96]), and DFS (0.62 [0.39-0.97]) versus surgery alone.
CONCLUSIONS
Our study suggested that perioperative therapy may be associated with better survival among patients undergoing surgical treatment of clinical stage III NSCLC.
PubMed: 38812106
DOI: 10.1111/1759-7714.15305 -
Science Advances May 2024Viruses, bacteria, and parasites frequently cause infections in the gastrointestinal tract, but traditional vaccination strategies typically elicit little or no mucosal...
Viruses, bacteria, and parasites frequently cause infections in the gastrointestinal tract, but traditional vaccination strategies typically elicit little or no mucosal antibody responses. Here, we report a strategy to effectively concentrate immunogens and adjuvants in gut-draining lymph nodes (LNs) to induce gut-associated mucosal immunity. We prepared nanoemulsions (NEs) based on biodegradable oils commonly used as vaccine adjuvants, which encapsulated a potent Toll-like receptor agonist and displayed antigen conjugated to their surface. Following intraperitoneal administration, these NEs accumulated in gut-draining mesenteric LNs, priming strong germinal center responses and promoting B cell class switching to immunoglobulin A (IgA). Optimized NEs elicited 10- to 1000-fold higher antigen-specific IgG and IgA titers in the serum and feces, respectively, compared to free antigen mixed with NE, and strong neutralizing antibody titers against severe acute respiratory syndrome coronavirus 2. Thus, robust gut humoral immunity can be elicited by exploiting the unique lymphatic collection pathways of the gut with a lymph-targeting vaccine formulation.
Topics: Animals; Immunity, Humoral; Mice; Gastrointestinal Tract; Lymphoid Tissue; Immunity, Mucosal; SARS-CoV-2; COVID-19; Antibodies, Viral; Lymph Nodes; Immunoglobulin A; COVID-19 Vaccines; Antibodies, Neutralizing; Female; B-Lymphocytes; Adjuvants, Vaccine; Mice, Inbred C57BL; Humans
PubMed: 38809992
DOI: 10.1126/sciadv.adn7786 -
Journal of Biomedical Research May 2024Tumor vaccines are a promising avenue in cancer immunotherapy. Despite the progress in targeting specific immune epitopes, tumor cells lacking them can evade treatment....
Tumor vaccines are a promising avenue in cancer immunotherapy. Despite the progress in targeting specific immune epitopes, tumor cells lacking them can evade treatment. Here, we aimed to construct an efficient tumor vaccine Vac-SM, utilizing shikonin (SKN) to induce immunogenic cell death (ICD) and ( ) as an immune adjuvant to enhance tumor vaccine efficacy. SKN demonstrated a dose-dependent and time-dependent cytotoxic effect on the tumor cell line as seen using the CCK-8 assay and induced ICD in tumor cells by detecting the expression of relevant indicators respectively. Compared to that in the control groups, Vac-SM injection in mouse subcutaneous metastatic tumors significantly inhibited tumor growth and distant tumor growth and improved survival rates. effectively induced bone marrow-derived dendritic cells (DC) maturation and activation and tumor-draining lymph nodes showed increased maturation of DC and a higher proportion of effector memory T-cell subsets with Vac-SM treatment, based on flow cytometry analysis results.Collectively, Vac-SM vaccine effectively induces ICD, improves antigen presentation by DC, activates a specific systemic antitumor T-cell immune response, exhibits favorable safety profile, and holds promise for clinical translation for local tumor immunotherapy.
PubMed: 38807377
DOI: 10.7555/JBR.38.20240049 -
Frontiers in Immunology 2024None of the typhoid Vi Polysaccharide (ViPS) subunit vaccines incorporate adjuvants, and the immunogenicity of ViPS vaccines (e.g. Typbar TCV and Typhim Vi) is in part...
None of the typhoid Vi Polysaccharide (ViPS) subunit vaccines incorporate adjuvants, and the immunogenicity of ViPS vaccines (e.g. Typbar TCV and Typhim Vi) is in part due to associated TLR4 ligands such as endotoxin present in these vaccines. Since endotoxin content in vaccines is variable and kept very low due to inherent toxicity, it was hypothesized that incorporating a defined amount of a non-toxic TLR4-ligand such as monophosphoryl lipid A in ViPS vaccines would improve their immunogenicity. To test this hypothesis, a monophosphoryl lipid A-based adjuvant formulation named Turbo was developed. Admixing Turbo with Typbar TCV (ViPS-conjugated to tetanus toxoid) increased the levels of anti-ViPS IgM, IgG1, IgG2b, IgG2a/c, and IgG3 in inbred and outbred mice. In infant mice, a single immunization with Turbo adjuvanted Typbar TCV resulted in a significantly increased and durable IgG response and improved the control of bacterial burden compared to mice immunized without Turbo. Similarly, when adjuvanted with Turbo, the antibody response and control of bacteremia were also improved in mice immunized with Typhim Vi, an unconjugated vaccine. The immunogenicity of unconjugated ViPS is inefficient in young mice and is lost in adult mice when immunostimulatory ligands in ViPS are removed. Nevertheless, when adjuvanted with Turbo, poorly immunogenic ViPS induced a robust IgG response in young and adult mice, and this was observed even under antigen-limiting conditions. These data suggest that incorporation of Turbo as an adjuvant will make typhoid vaccines more immunogenic regardless of their intrinsic immunogenicity or conjugation status and maximize the efficacy across all ages.
Topics: Animals; Typhoid-Paratyphoid Vaccines; Mice; Toll-Like Receptor 4; Vaccines, Subunit; Antibodies, Bacterial; Adjuvants, Immunologic; Lipid A; Typhoid Fever; Immunoglobulin G; Female; Ligands; Polysaccharides, Bacterial; Immunogenicity, Vaccine; Adjuvants, Vaccine; Salmonella typhi; Mice, Inbred BALB C
PubMed: 38799439
DOI: 10.3389/fimmu.2024.1383476