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Risk Analysis : An Official Publication... Jul 2024Europe faces regular introductions and reintroductions of bluetongue virus (BTV) serotypes, most recently exemplified by the incursion of serotype 3 in the Netherlands....
Europe faces regular introductions and reintroductions of bluetongue virus (BTV) serotypes, most recently exemplified by the incursion of serotype 3 in the Netherlands. Although the long-distance wind dispersal of the disease vector, Culicoides spp., is recognized as a virus introduction pathway, it remains understudied in risk assessments. A Quantitative Risk Assessment framework was developed to estimate the risk of BTV-3 incursion into mainland Europe from Sardinia, where the virus has been present since 2018. We used an atmospheric transport model (HYbrid Single-Particle Lagrangian Integrated Trajectory) to infer the probability of airborne dispersion of the insect vector. Epidemiological disease parameters quantified the virus prevalence in vector population in Sardinia and its potential first transmission after introduction in a new area. When assuming a 24h maximal flight duration, the risk of BTV introduction from Sardinia is limited to the Mediterranean Basin, mainly affecting the southwestern area of the Italian Peninsula, Sicily, Malta, and Corsica. The risk extends to the northern and central parts of Italy, Balearic archipelago, and mainland France and Spain, mostly when maximal flight duration is longer than 24h. Additional knowledge on vector flight conditions and Obsoletus complex-specific parameters could improve the robustness of the model. Providing both spatial and temporal insights into BTV introduction risks, our framework is a key tool to guide global surveillance and preparedness against epizootics.
PubMed: 38955987
DOI: 10.1111/risa.14345 -
Journal of Cancer Research and Clinical... Jul 2024To explore the effect and mechanism of relaxin (RLX) in the growth and metastasis of livercancer after combination treatment with transarterial chemoembolization (TACE).
OBJECTIVE
To explore the effect and mechanism of relaxin (RLX) in the growth and metastasis of livercancer after combination treatment with transarterial chemoembolization (TACE).
MATERIALS AND METHODS
HCCLM3 and Huh-7 cells were adopted to evaluate the effect of tumor proliferation, migration, and invasion after RLX administration in vitro. The rabbit VX2 model was used to evaluate the biosafety, doxorubicin penetration, local tumor response, tumor metastasis, and survival benefit of RLX combined with TACE treatment.
RESULTS
RLX did not affect the proliferation, migration, or invasion of HCCLM3 and Huh-7 cells, and the expression of E-cadherin and HIF-1α also remained unchanged while the MMP-9 protein was upregulated in vitro. In the rabbit VX2 model, compared to the normal saline group (NS), RLX group (RLX) and TACE mono-therapy group (TACE), the group that received TACE combined with RLX (TACE + RLX) showed an improved local tumor response and survival benefit. Furthermore, TACE combined with RLX was found to reduce tumor metastasis. This combination therapy reduced the fibrotic extracellular matrix in the tumor microenvironment, allowing for better penetration of doxorubicin, improved infiltration of CD8+ T cells and affected the secretion of cytokines. Additionally, RLX combined with TACE was able to decrease the expression of HIF-1α and PD-L1. The biosafety of TACE combined with RLX was also confirmed.
CONCLUSION
RLX synergized with TACE by mitigating the fibrotic extracellular matrix and tumor hypoxic microenvironment, improving the therapeutic effect and inhibiting metastasis during the treatment of liver cancer.
Topics: Animals; Chemoembolization, Therapeutic; Rabbits; Relaxin; Liver Neoplasms; Doxorubicin; Humans; Combined Modality Therapy; Cell Proliferation; Cell Line, Tumor; Disease Models, Animal; Carcinoma, Hepatocellular; Neoplasm Metastasis
PubMed: 38955827
DOI: 10.1007/s00432-024-05864-6 -
Zhonghua Er Ke Za Zhi = Chinese Journal... Jul 2024
Review
Topics: Nephritis, Hereditary; Genetic Therapy; Humans; Collagen Type IV; Animals; Disease Models, Animal; Mutation; Genetic Vectors; Gene Transfer Techniques; Mice; Basement Membrane
PubMed: 38955691
DOI: 10.3760/cma.j.cn112140-20240222-00118 -
Physiological Reports Jul 2024Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 cytokine family, has renoprotective effects in mouse models of acute kidney disease and tubulointerstitial...
Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 cytokine family, has renoprotective effects in mouse models of acute kidney disease and tubulointerstitial fibrosis, but its role in glomerular disease is unknown. To address this, we used the mouse model of nephrotoxic nephritis to test the hypothesis that CT-1 also has a protective role in immune-mediated glomerular disease. Using immunohistochemistry and analysis of single-cell RNA-sequencing data of isolated glomeruli, we demonstrate that CT-1 is expressed in the glomerulus in male mice, predominantly in parietal epithelial cells and is downregulated in mice with nephrotoxic nephritis. Furthermore, analysis of data from patients revealed that human glomerular disease is also associated with reduced glomerular CT-1 transcript levels. In male mice with nephrotoxic nephritis and established proteinuria, administration of CT-1 resulted in reduced albuminuria, prevented podocyte loss, and sustained plasma creatinine, compared with mice administered saline. CT-1 treatment also reduced fibrosis in the kidney cortex, peri-glomerular macrophage accumulation and the kidney levels of the pro-inflammatory mediator complement component 5a. In conclusion, CT-1 intervention therapy delays the progression of glomerular disease in mice by preserving kidney function and inhibiting renal inflammation and fibrosis.
Topics: Animals; Male; Cytokines; Mice; Kidney Glomerulus; Mice, Inbred C57BL; Disease Models, Animal; Humans; Fibrosis; Glomerulonephritis
PubMed: 38955668
DOI: 10.14814/phy2.16129 -
The Journal of Pharmacology and... Jul 2024People with sickle cell disease (SCD) often experience chronic pain as well as unpredictable episodes of acute pain, which significantly affect their quality of life and...
People with sickle cell disease (SCD) often experience chronic pain as well as unpredictable episodes of acute pain, which significantly affect their quality of life and life expectancy. Current treatment strategies for SCD-associated pain primarily rely on opioid analgesics, which have limited efficacy and cause serious adverse effects. Cannabis has emerged as a potential alternative, yet its efficacy remains uncertain. In this study, we investigated the antinociceptive effects of Δ-tetrahydrocannabinol (THC), cannabis' intoxicating constituent, in male HbSS mice, which express >99% human sickle hemoglobin, and male HbAA mice, which express normal human hemoglobin A, as a control. Acute THC administration (0.1-3 mg-kg, intraperitoneal, i.p.) dose-dependently reduced mechanical and cold hypersensitivity in HbSS, but not HbAA mice. In the tail-flick assay, THC (1 and 3 mg-kg, i.p.) produced substantial antinociceptive effects in HbSS mice. By contrast, THC (1 mg-kg, i.p.) did not alter anxiety-like behavior (elevated plus maze) or long-term memory (24-h novel object recognition). Subchronic THC treatment (1 and 3 mg-kg, i.p.) provided sustained relief of mechanical hypersensitivity but led to tolerance in cold hypersensitivity in HbSS mice. Together, the findings identify THC as a possible therapeutic option for the management of chronic pain in SCD. Further research is warranted to elucidate its mechanism of action and possible interaction with other cannabis constituents. The study explores THC's efficacy in alleviating pain in sickle cell disease (SCD) using a humanized mouse model. Findings indicate that acute THC administration reduces mechanical and cold hypersensitivity in SCD mice without impacting emotional and cognitive dysfunction. Subchronic THC treatment offers sustained relief of mechanical hypersensitivity but leads to cold hypersensitivity tolerance. These results offer insights into THC's potential as an alternative pain management option in SCD, highlighting both its benefits and limitations.
PubMed: 38955494
DOI: 10.1124/jpet.124.002285 -
Journal For Immunotherapy of Cancer Jul 2024Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood...
BACKGROUND
Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood cancers. Nevertheless, over 40% of B cell malignancy patients experience a relapse after CAR-T therapy, likely due to inadequate persistence of the modified T cells in the body. IL15, known for its pro-survival and proliferative properties, has been suggested for incorporation into the fourth generation of CAR-T cells to enhance their persistence. However, the potential systemic toxicity associated with this cytokine warrants further evaluation.
METHODS
We analyzed the persistence, antitumor efficacy and potential toxicity of anti-mouse CD19 CAR-T cells which express a membrane-bound IL15-IL15Rα chimeric protein (CD19/mbIL15q CAR-T), in BALB/c mice challenged with A20 tumor cells as well as in NSG mice.
RESULTS
Conventional CD19 CAR-T cells showed low persistence and poor efficacy in BALB/c mice treated with mild lymphodepletion regimens (total body irradiation (TBI) of 1 Gy). CD19/mbIL15q CAR-T exhibits prolonged persistence and enhanced in vivo efficacy, effectively eliminating established A20 B cell lymphoma. However, this CD19/mbIL15q CAR-T displays important long-term toxicities, with marked splenomegaly, weight loss, transaminase elevations, and significant inflammatory findings in some tissues. Mice survival is highly compromised after CD19/mbIL15q CAR-T cell transfer, particularly if a high TBI regimen is applied before CAR-T cell transfer.
CONCLUSION
Tethered IL15-IL15Rα augments the antitumor activity of CD19 CAR-T cells but displays long-term toxicity in immunocompetent mice. Inducible systems to regulate IL15-IL15Rα expression could be considered to control this toxicity.
Topics: Animals; Mice; Antigens, CD19; Interleukin-15; Immunotherapy, Adoptive; Humans; Disease Models, Animal; Cell Line, Tumor; Female; Interleukin-15 Receptor alpha Subunit; Receptors, Chimeric Antigen; Lymphoma; Mice, Inbred BALB C; T-Lymphocytes
PubMed: 38955421
DOI: 10.1136/jitc-2023-008572 -
International Journal of Hyperthermia :... 2024Cryoablation (Cryo) is a minimally invasive treatment for tumors. Cryo can activate the body's immune response, although it is typically weak. The immune response...
BACKGROUND
Cryoablation (Cryo) is a minimally invasive treatment for tumors. Cryo can activate the body's immune response, although it is typically weak. The immune response induced by Cryo in hepatocellular carcinoma (HCC) is poorly understood. PD-1 and CTLA-4 monoclonal antibodies are immune checkpoint inhibitors used in immunotherapy for tumors. The combined use of these antibodies with Cryo may enhance the immune effect.
METHODS
A Balb/c mouse model of HCC was established and treated with Cryo, immune checkpoint blockade (ICB), or Cryo + ICB (combination therapy). The growth trend of right untreated tumors and survival time of mice were determined. The expression of apoptosis-related proteins was detected by Western blot (WB) assay. The percentages of immune cells and immunosuppressive cells were analyzed by flow cytometry. The numbers of infiltrating T lymphocytes were checked by immunohistochemistry, and the levels of T-cell-associated cytokines were detected by Quantitative real-time Polymerase Chain Reaction (qRT-PCR) assays and Enzyme-Linked Immunosorbent Assays (ELISA) assays.
RESULTS
Cryo + ICB inhibited the growth of right untreated tumors, promoted tumor cell apoptosis, and prolonged the survival time of mice. Local T-cell infiltration in right tumor tissues increased after the combination therapy, while the number of immunosuppressive cells was significantly reduced. In addition, the combination therapy may induce the production of multiple Th1-type cytokines but reduce the production of Th2-type cytokines.
CONCLUSIONS
Cryo can activate CD8 and CD4 T-cell immune responses. Cryo + ICB can relieve the immunosuppressive tumor microenvironment and shift the Th1/Th2 balance toward Th1 dominance, further enhancing the Cryo-induced T-cell immune response and resulting in a stronger antitumor immune response.
Topics: Animals; Carcinoma, Hepatocellular; Mice; Liver Neoplasms; Cryosurgery; Mice, Inbred BALB C; Immune Checkpoint Inhibitors; Disease Models, Animal; Cell Line, Tumor
PubMed: 38955354
DOI: 10.1080/02656736.2024.2373319 -
Biomedical Materials (Bristol, England) Jul 2024This study aimed to develop and optimize karanjin-loaded ethosomal nanogel formulation and evaluate its efficacy in alleviating symptoms of psoriasis in an animal...
Karanjin-loaded soya lecithin-based ethosomal nanogel for the therapeutic intervention of psoriasis: formulation development, factorial design based-optimization, in vitro and in vivo assessment.
This study aimed to develop and optimize karanjin-loaded ethosomal nanogel formulation and evaluate its efficacy in alleviating symptoms of psoriasis in an animal model induced by imiquimod.. These karanjin-loaded ethosomal nanogel, were formulated to enhance drug penetration into the skin and its epidermal retention. Karanjin was taken to formulate ethosomes due to its potential ani-psoriatic activity. Ethosomes were formulated using the cold method using 32 full factorial designs to optimize the formulation components. 9 batches were prepared using two independent variables X1: concentration of ethanol and X2: concentration of phospholipid whereas vesicle size (Y1) and percentage entrapment efficiency (Y2) were selected as dependent variables. All the dependent variables were found to be statistically significant. The optimized ethosomal suspension (B3) exhibited a vesicle size of 334±2.89 nm with an entrapment efficiency of 94.88 ± 1.24% and showed good stability. The morphology of vesicles appeared spherical with smooth surfaces through Transmission Electron Microscopy (TEM) analysis. X-ray diffraction (XRD) analysis confirmed that the drug existed in an amorphous state within the ethosomal formulation. The optimized ethosome was incorporated into carbopol 934 to develop nanogel for easy application on the skin. The nanogel underwent characterization for various parameters including spreadability, viscosity, pH, extrudability, and percentage drug content. The ethosomal formulation remarkably enhanced the skin permeation of karanjin and increased epidermal retention of the drug in psoriatic skin compared to marketed preparation and pure drug. A skin retention study showed that ethosomal nanogel formulation has 48.33% epidermal retention in 6h. In vivo, the anti-psoriatic activity of karanjin ethosomal nanogel demonstrated significant improvement in psoriasis, indicated by a gradual decrease in skin thickness and scaling as reflected in the PSI grading. Therefore, the prepared ethosomal nanogel is a potential vehicle for improved topical delivery of karanjin for better treatment of psoriasis. .
PubMed: 38955335
DOI: 10.1088/1748-605X/ad5e51 -
Ageing Research Reviews Jun 2024Magnolia officinalis, a traditional herbal medicine widely used in clinical practice, exerts antibacterial, anti-tumor, anti-inflammatory, antioxidant, and anti-aging... (Review)
Review
BACKGROUND
Magnolia officinalis, a traditional herbal medicine widely used in clinical practice, exerts antibacterial, anti-tumor, anti-inflammatory, antioxidant, and anti-aging activities. Neolignans are the main active ingredients of M. officinalis and exert a wide range of pharmacological effects, including anti-Alzheimer's disease (AD) activity.
OBJECTIVE
To summarize the published data on the therapeutic effect and mechanism of neolignans on AD in vivo and in vitro.
METHODS
PubMed, Web of Science, Google Scholar, and Scopus were systematically reviewed (up to March 1, 2024) for pre-clinical studies.
RESULTS
M. officinalis-derived neolignans (honokiol, magnolol, 4-O-methylhonokiol, and obovatol) alleviated behavioral abnormalities, including learning and cognitive impairments, in AD animal models. Mechanistically, neolignans inhibited Aβ generation or aggregation, neuroinflammation, and acetylcholinesterase activity; promoted microglial phagocytosis and anti-oxidative stress; alleviated mitochondrial dysfunction and energy metabolism, as well as anti-cholinergic deficiency; and regulated intestinal flora. Furthermore, neolignans may achieve neuroprotection by regulating different molecular pathways, including the NF-κB, ERK, AMPK/mTOR/ULK1, and cAMP/PKA/CREB pathways.
CONCLUSIONS
Neolignans exert anti-AD effects through multiple mechanisms and pathways. However, the exact targets, pharmacokinetics, safety, and clinical efficacy in patients with AD need further investigation in multi-center clinical case-control studies.
PubMed: 38955265
DOI: 10.1016/j.arr.2024.102398 -
Proceedings. Biological Sciences Jul 2024Vocal turn-taking has been described in a diversity of species. Yet, a model that is able to capture the various processes underlying this social behaviour across...
Vocal turn-taking has been described in a diversity of species. Yet, a model that is able to capture the various processes underlying this social behaviour across species has not been developed. To this end, here we recorded a large and diverse dataset of marmoset monkey vocal behaviour in social contexts comprising one, two and three callers and developed a model to determine the keystone factors that affect the dynamics of these natural communicative interactions. Notably, marmoset turn-taking did not abide by coupled-oscillator dynamics, but rather call timing was overwhelmingly stochastic in these exchanges. Our features-based model revealed four key factors that encapsulate the majority of patterns evident in the behaviour, ranging from internal processes, such as particular states of the individual driving increased calling, to social context-driven suppression of calling. These findings indicate that marmoset vocal turn-taking is affected by a broader suite of mechanisms than previously considered and that our model provides a predictive framework with which to further explicate this natural behaviour at both the behavioural and neurobiological levels, and for direct comparisons with the analogous behaviour in other species.
Topics: Animals; Callithrix; Vocalization, Animal; Social Behavior; Male; Female; Models, Biological
PubMed: 38955229
DOI: 10.1098/rspb.2024.0150