Accelerated full-thickness skin wound tissue regeneration by self-crosslinked chitosan hydrogel films reinforced by oxidized CNC-AgNPs stabilized Pickering emulsion for quercetin delivery.

BACKGROUND: The non-toxic self-crosslinked hydrogel films designed from biocompatible materials allow for controlled drug release and have gathered remarkable attention from healthcare professionals as wound dressing materials. Thus, in the current study the chitosan (CS) film is infused with oil-in-water Pickering emulsion (PE) loaded with bioactive compound quercetin (Qu) and stabilized by dialdehyde cellulose nanocrystal-silver nanoparticles (DCNC-AgNPs). The DCNC-AgNPs play a dual role in stabilizing PE and are involved in the self-crosslinking with CS films. Also, this film could combine the advantage of the controlled release and synergistic wound-healing effect of Qu and AgNPs. RESULTS: The DCNC-AgNPs were synthesized using sodium periodate oxidation of CNC. The DCNC-AgNPs were used to stabilize oil-in-water PE loaded with Qu in its oil phase by high speed homogenization. Stable PEs were prepared by 20% v/v oil: water ratio with maximum encapsulation of Qu in the oil phase. The Qu-loaded PE was then added to CS solution (50% v/v) to prepare self-crosslinked films (CS-PE-Qu). After grafting CS films with PE, the surface and cross-sectional SEM images show an inter-penetrated network within the matrix between DCNC and CS due to the formation of a Schiff base bond between the reactive aldehyde groups of DCNC-AgNPs and amino groups of CS. Further, the addition of glycerol influenced the extensibility, swelling ratio, and drug release of the films. The fabricated CS-PE-Qu films were analyzed for their wound healing and tissue regeneration potential using cell scratch assay and full-thickness excisional skin wound model in mice. The as-fabricated CS-PE-Qu films showed great biocompatibility, increased HaCat cell migration, and promoted collagen synthesis in HDFa cells. In addition, the CS-PE-Qu films exhibited non-hemolysis and improved wound closure rate in mice compared to CS, CS-Qu, and CS-blank PE. The H&E staining of the wounded skin tissue indicated the wounded tissue regeneration in CS-PE-Qu films treated mice. CONCLUSION: Results obtained here confirm the wound healing benefits of CS-PE-Qu films and project them as promising biocompatible material and well suited for full-thickness wound healing in clinical applications.

Salvia miltiorrhiza bunge extracts: a promising source for anti-atopic dermatitis activity.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory condition characterized by the accumulation of reactive oxygen species and the expression of inflammatory factors. Regarding its anti-atopic activity, numerous traditional medicinal materials and secondary metabolic products play pivotal roles in modulating the associated mechanisms. METHODS: This study aimed to utilize Salvia miltiorrhiza Bunge (SMB) as an anti-AD source. In-vitro activity assessments and qualitative and quantitative analyses using UPLC-TQ-MS/MS and HPLC-DAD were conducted in two cultivars ('Dasan' and 'Kosan'). Statistical analysis indicated that the profiles of their secondary metabolites contribute significantly to their pharmacological properties. Consequently, bio-guided fractionation was undertaken to figure out the distinct roles of the secondary metabolites present in SMB. RESULTS: Comparative study of two cultivars indicated that 'Dasan', having higher salvianolic acid A and B, exhibited stronger antioxidant and anti-inflammatory activities. Meanwhile, 'Kosan', containing higher tanshinones, showed higher alleviating activities on anti-AD related genes in mRNA levels. Additionally, performed bio-guided fractionation re-confirmed that the hydrophilic compounds of SMB can prevent AD by inhibiting accumulation of ROS and suppressing inflammatory factors and the lipophilic components can directly inhibit AD. CONCLUSIONS: SMB was revealed as a good source for anti-AD activity. Several bioactive compounds were identified from the UPLC-TQ-MS/MS and different compounds content was linked to biological activities. Characterization of these compounds may be helpful to understand differential role of secondary metabolites from SMB on alleviation of AD.

Protective effect of zinc oxide nanoparticles synthesized using Cassia alata for DSS-induced ulcerative colitis in mice model.

The most prevalent form of inflammatory bowel disease (IBD), ulcerative colitis (UC), is characterized by persistent inflammation of the colorectal mucosa. It is asymptomatic, whereas Crohn's disease (CD) causes patchy lesions in the gastrointestinal tract. Men and women suffer equally from ulcerative colitis, which usually strikes in the second and third decades of life and becomes more common in senior citizens. In the present study, we produced zinc oxide nanoparticles using the natural herbal plant, Cassia alata. Zinc oxide nanoparticles have remarkable antimicrobial and antitumor benefits in the field of biomedical science. Furthermore, the synthesized zinc oxide nanoparticles (ZnO NPs) were characterized using UV, XRD, FTIR, and SEM analyses. The XRD analysis confirmed the crystallite nature and purity of the synthesized nanoparticles. Zinc oxide nanoparticles with a uniform size and partially agglomerated morphology were verified by SEM analysis. We investigated the protective effects of environmentally friendly zinc oxide nanoparticles in dextran sodium sulfate-induced ulcerative colitis mouse models. Green synthesized Cassia alata zinc oxide nanoparticles (CA ZnO NPs) reversed weight loss, disease activity index, colon shortening, and colon histological damage. Zinc oxide nanoparticles reduce hypersensitivity, oxidative stress, and inflammation, and protect the mucosal layer. Green synthesized CA ZnO NPs demonstrated protection against dextran sodium sulfate-induced ulcerative colitis via anti-inflammatory activity.

Comparison of CAR T-cell vs. bispecific antibody as third- or later-line large B-cell lymphoma therapy: A Meta-analysis.

This meta-analysis evaluates the efficacy and safety of chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We searched MEDLINE, Embase, and Cochrane databases until July 2023 for trials assessing CAR T-cell therapies and CD20×CD3 bispecific antibodies as third- or subsequent-line in R/R DLBCL. Random effects models estimated the complete response (CR) rate and secondary outcomes, with meta-regressions adjusting for relevant covariates. Sixteen studies comprising 1,347 patients were included in the pooled analysis. The pooled CR rate for bispecific antibodies was 0.36 (95% CI, 0.29 to 0.43), compared to 0.51 (0.46 to 0.56) for CAR T-cell therapy (p<0.01). This superiority persisted when comparing the CAR-T naïve patients within the bispecific antibody group, CR rate of 0.37 (0.32 to 0.43). Multivariable meta-regression also revealed better efficacy of CAR-T with adjustment for the proportion of double-hit lymphoma. The pooled one-year progression-free survival rate mirrored these findings (0.32 [0.26 to 0.38] vs 0.44 [0.41 to 0.48], p<0.01). For adverse events of ≥ grade 3, the bispecific antibody had incidences of 0.02 (0.01 to 0.04) for cytokine release syndrome, 0.01 (0.00 to 0.01) for neurotoxicity, and 0.10 (0.03 to 0.16) for infections. The CAR-T cell had rates of 0.08 (0.03 to 0.12), 0.11 (0.06 to 0.17), and 0.17 (0.11 to 0.22), respectively, with significant differences observed in the first two categories. In summary, CAR-T cell therapy outperformed bispecific antibody in achieving higher CR rates, though with an increase in severe adverse events.

Investigation of the myopic outcomes of the newer intraocular lens power calculation formulas in Korean patients with long eyes.

This study investigated the underlying causes of the myopic outcomes of the optic-based newer formulas (Barrett Universal II, EVO 2.0, Kane, Hoffer-QST and PEARL-DGS) in long Korean eyes with Alcon TFNT intraocular lens (IOL) implantation. Postoperative data from 3100 randomly selected eyes of 3100 patients were analyzed to compare the reference back-calculated effective lens positions (ELPs) based on the Haigis formula using conventional axial length (AL) and Cooke-modified AL (CMAL) with the predicted ELP of each single- and triple-optimized Haigis formula applied to AL- and CMAL. Contrary to the AL-applied Haigis formula, the predicted ELP curve of the CMAL-applied, single-optimized Haigis formula, simulating the methods of the newer formulas, exhibited a significant upward deviation from the back-calculated ELP in long eyes. The relationship between the AL and anterior chamber depth in our long-eyed population differed from that in the base population of the PEARL-DGS formula. The myopic outcomes in long eyes appeared to stem from the substantial overestimation of the postoperative IOL position with AL modification, leading to the implantation of inappropriately higher-powered IOLs. This discrepancy may be attributed to the ethnic differences in ocular biometrics, particularly the relatively smaller anterior segment in East Asian patients with long AL.

Genomic Insights into Dementia: Precision Medicine and the Impact of Gene-Environment Interaction.

The diagnosis, treatment, and management of dementia provide significant challenges due to its chronic cognitive impairment. The complexity of this condition is further highlighted by the impact of gene-environment interactions. A recent strategy combines advanced genomics and precision medicine methods to explore the complex genetic foundations of dementia. Utilizing the most recent research in the field of neurogenetics, the importance of precise genetic data in explaining the variation seen in dementia patients can be investigated. Gene-environment interactions are important because they influence genetic susceptibilities and aid in the development and progression of dementia. Modified to each patient's genetic profile, precision medicine has the potential to detect groups at risk and make previously unheard-of predictions about the course of diseases. Precision medicine techniques have the potential to completely transform treatment and diagnosis methods. Targeted medications that target genetic abnormalities will probably appear, providing the possibility for more efficient and customized medical interventions. Investigating the relationship between genes and the environment may lead to preventive measures that would enable people to change their surroundings and minimize the risk of dementia, leading to the improved lifestyle of affected people. This paper provides a comprehensive overview of the genomic insights into dementia, emphasizing the pivotal role of precision medicine, and gene-environment interactions.

Comparison of the formula accuracy for calculating multifocal intraocular lens power: a single center retrospective study in Korean patients.

This study evaluated the accuracy of newer formulas (Barrett Universal II, EVO 2.0, Kane, Hoffer QST, and PEARL-DGS) and the Haigis formula in Korean patients with the Alcon TFNT multifocal intraocular lens. In total, 3100 randomly selected eyes of 3100 patients were retrospectively reviewed. After constant optimization, the standard deviation (SD) of the prediction error was assessed for the entire group, and the root mean square error was compared for short and long axial length (AL) subgroup analysis. The Cooke-modified AL (CMAL) was experimentally applied to the Haigis formula. All the newer formulas performed well, but they did not significantly outperform the Haigis formula. In addition, all the newer formulas exhibited significant myopic outcomes (- 0.23 to - 0.29 diopters) in long eyes. Application of the CMAL to the Haigis formula with single constant optimization produced similar behavior and higher correlation with the newer formulas. The CMAL-applied triple-optimized Haigis formula yielded a substantially smaller SD, even superior to the Barrett and Hoffer QST formulas. The AL modification algorithms such as the CMAL used in newer formulas to cope with optical biometry's overestimation of the AL in long eyes seemed to overcompensate, particularly in the long eyes of the East Asian population.

Peptide-Drug Conjugate with Statistically Designed Transcellular Peptide for Psoriasis-Like Inflammation.

Peptide-drug conjugates (PDCs) are a promising class of drug delivery systems that utilize covalently conjugated carrier peptides with therapeutic agents. PDCs offer several advantages over traditional drug delivery systems including enhanced target engagement, improved bioavailability, and increased cell permeability. However, the development of efficient transcellular peptides capable of effectively transporting drugs across biological barriers remains an unmet need. In this study, physicochemical criteria based on cell-penetrating peptides are employed to design transcellular peptides derived from an antimicrobial peptides library. Among the statistically designed transcellular peptides (SDTs), SDT7 exhibits higher skin permeability, faster kinetics, and improved cell permeability in human keratinocyte cells compared to the control peptide. Subsequently, it is found that 6-Paradol (PAR) exhibits inhibitory activity against phosphodiesterase 4, which can be utilized for an anti-inflammatory PDC. The transcellular PDC (SDT7-conjugated with PAR, named TM5) is evaluated in mouse models of psoriasis, exhibiting superior therapeutic efficacy compared to PAR alone. These findings highlight the potential of transcellular PDCs (TDCs) as a promising approach for the treatment of inflammatory skin disorders.

ThermOxshield ion pair self assembly unleashing suppressed release.

Poly (acrylic acid) (PAA), an anionic polymer was used to prepare ion pair self-assembly (IPSAM) with 4-(methylthio)aniline (MTA), a hydrophobic counter ion, which is responsive to temperature and oxidation. The IPSAM was formed when the carboxylic to amino group molar ratio was 7/3-5/5. The structure of the IPSAM nanoparticle was spherical whose diameter was 30-40 nm on the TEM images. The PAA/MTA ion pair showed the upper critical solution temperature (UCST) that hiked with increasing MTA content. When the MTA of the ion pair was oxidized by H2O2, the UCST was also increased. The amphiphilic property of the ion pair was responsible for interface activity which declined upon the oxidation of the MTA. The surface tension was low for the ratio of PAA/MTA (5/5), which made the 5/5 ratio suitable for further studies. The interaction between PAA and MTA, which was ionic, and the oxidation of MTA was confirmed by FT-IR spectroscopy. The release of payload (i.e. Nile red) in IPSAM was restrained below the UCST but it was triggered above the phase transition temperature possibly due to the disintegration of the IPSAM whereas on MTA oxidation the release was shielded due to more hydrophobicity. The release was found to be higher in tumor environment temperature which could be controlled with the input concentration of H2O2 giving a stable IPSAM. The cell viability results showed that IPSAM has no significant cytotoxicity and can serve as a drug carrier for stimulus-response.

Machine Learning Algorithms Predict Successful Weaning From Mechanical Ventilation Before Intubation: Retrospective Analysis From the Medical Information Mart for Intensive Care IV Database.

BACKGROUND: The prediction of successful weaning from mechanical ventilation (MV) in advance of intubation can facilitate discussions regarding end-of-life care before unnecessary intubation. OBJECTIVE: We aimed to develop a machine learning-based model that predicts successful weaning from ventilator support based on routine clinical and laboratory data taken before or immediately after intubation. METHODS: We used the Medical Information Mart for Intensive Care IV database, which is an open-access database covering 524,740 admissions of 382,278 patients in Beth Israel Deaconess Medical Center, United States, from 2008 to 2019. We selected adult patients who underwent MV in the intensive care unit (ICU). Clinical and laboratory variables that are considered relevant to the prognosis of the patient in the ICU were selected. Data collected before or within 24 hours of intubation were used to develop machine learning models that predict the probability of successful weaning within 14 days of ventilator support. Developed models were integrated into an ensemble model. Performance metrics were calculated by 5-fold cross-validation for each model, and a permutation feature importance and Shapley additive explanations analysis was conducted to better understand the impacts of individual variables on outcome prediction. RESULTS: Of the 23,242 patients, 19,025 (81.9%) patients were successfully weaned from MV within 14 days. Using the preselected 46 clinical and laboratory variables, the area under the receiver operating characteristic curve of CatBoost classifier, random forest classifier, and regularized logistic regression classifier models were 0.860 (95% CI 0.852-0.868), 0.855 (95% CI 0.848-0.863), and 0.823 (95% CI 0.813-0.832), respectively. Using the ensemble voting classifier using the 3 models above, the final model revealed the area under the receiver operating characteristic curve of 0.861 (95% CI 0.853-0.869), which was significantly better than that of Simplified Acute Physiology Score II (0.749, 95% CI 0.742-0.756) and Sequential Organ Failure Assessment (0.588, 95% CI 0.566-0.609). The top features included lactate and anion gap. The model's performance achieved a plateau with approximately the top 21 variables. CONCLUSIONS: We developed machine learning algorithms that can predict successful weaning from MV in advance to intubation in the ICU. Our models can aid the appropriate management for patients who hesitate to decide on ventilator support or meaningless end-of-life care.

Phytochemical Investigation of Equisetum arvense and Evaluation of Their Anti-Inflammatory Potential in TNFα/INFγ-Stimulated Keratinocytes.

Equisetum arvense L. (Equisetaceae), widely known as 'horsetail', is a perennial plant found extensively across Asia. Extracts of E. arvense have been used in traditional medicine, particularly for the treatment of inflammatory disorders. This study aimed to determine the phytochemical compounds in E. arvense ethanolic extract and their anti-inflammatory properties. Subsequently, we isolated and identified nine secondary metabolites, including kaempferol 3,7-di-O-ß-D-glucopyranoside (1), icariside B2 (2), (Z)-3-hexenyl ß-D-glucopyranoside (3), luteolin 5-O-ß-D-glucopyranoside (4), 4-O-ß-D-glucopyranosyl caffeic acid (5), clemastanin B (6), 4-O-caffeoylshikimic acid (7), (7S,8S)-threo-7,9,9'-trihydroxy-3,3'-dimethoxy-8-O-4'-neolignan-4-O-ß-D-glucopyranoside (8), and 3-O-caffeoylshikimic acid (9). The chemical structures of the isolated compounds (1-9) were elucidated using HR-ESI-MS data, NMR spectra, and ECD data. Next, the anti-inflammatory effects of the isolates were evaluated in tumor necrosis factor (TNF)α/interferon (IFN)γ-induced HaCaT, a human keratinocyte cell line. Among the isolates, compound 3 showed the highest inhibitory effect on the expression of pro-inflammatory chemokines, followed by compounds 6 and 8. Correspondingly, the preceding isolates inhibited TNFα/IFNγ-induced activation of pro-inflammatory transcription factors, signal transducer and activator of transcription 1, and nuclear factor-κB. Collectively, E. arvense could be employed for the development of prophylactic or therapeutic agents for improving dermatitis.

Reactive Disperse Dyes Bearing Various Blocked Isocyanate Groups for Digital Textile Printing Ink.

Wastewater management is of considerable economic and environmental importance for the dyeing industry. Digital textile printing (DTP), which is based on sublimation transfer and does not generate wastewater, is currently being explored as an inkjet-based method of printing colorants onto fabric. It finds wide industrial applications with most poly(ethylene terephthalate) (PET) and nylon fibers. However, for additional industrial applications, it is necessary to use natural fibers, such as cotton. Therefore, to expand the applicability of DTP, it is essential to develop a novel reactive disperse dye that can interact with the fabric. In this study, we introduced a blocked isocyanate functional group into the dye to enhance binding to the fabric. The effect of sublimation transfer on fabrics as a function of temperature was compared using the newly synthesized reactive disperse dyes with different blocking groups based on pyrazole derivatives, such as pyrazole (Py), di-methylpyrazole (DMPy), and di-tert-butylpyrazole (DtBPy). Fabrics coated with the new reactive disperse dyes, including PET, nylon, and cotton, were printed at 190 °C, 200 °C, and 210 °C using thermal transfer equipment. In the case of the synthesized DHP-A dye on cotton at 210 °C, the color strength was 2.1, which was higher than that of commercial dyes and other synthesized dyes, such as DMP-A and DTP-A. The fastness values of the synthesized DHP-A were measured on cotton, and it was found that the washing and light fastness values on cotton are higher than those of commercial dyes. This study confirmed the possibility of introducing isocyanate groups into reactive disperse dyes.

The Cannabinoids, CBDA and THCA, Rescue Memory Deficits and Reduce Amyloid-Beta and Tau Pathology in an Alzheimer's Disease-like Mouse Model.

Most studies related to hemp are focused on Cannabidiol (CBD) and Tetrahydrocannabinol (THC); however, up to 120 types of phytocannabinoids are present in hemp. Hemp leaves contain large amounts of Cannabidiolic acid (CBDA) and Tetrahydrocannabinolic acid (THCA), which are acidic variants of CBD and THC and account for the largest proportion of CBDA. In recent studies, CBDA exhibited anti-hyperalgesia and anti-inflammatory effects. THCA also showed anti-inflammatory and neuroprotective effects that may be beneficial for treating neurodegenerative diseases. CBDA and THCA can penetrate the blood-brain barrier (BBB) and affect the central nervous system. The purpose of this study was to determine whether CBDA and THCA ameliorate Alzheimer's disease (AD)-like features in vitro and in vivo. The effect of CBDA and THCA was evaluated in the Aß1-42-treated mouse model. We observed that Aß1-42-treated mice had more hippocampal Aß and p-tau levels, pathological markers of AD, and loss of cognitive function compared with PBS-treated mice. However, CBDA- and THCA-treated mice showed decreased hippocampal Aß and p-tau and superior cognitive function compared with Aß1-42-treated mice. In addition, CBDA and THCA lowered Aß and p-tau levels, alleviated calcium dyshomeostasis, and exhibited neuroprotective effects in primary neurons. Our results suggest that CBDA and THCA have anti-AD effects and mitigate memory loss and resilience to increased hippocampal Ca2+, Aß, and p-tau levels. Together, CBDA and THCA may be useful therapeutic agents for treating AD.

Ca2+-Permeable TRPV1 Receptor Mediates Neuroprotective Effects in a Mouse Model of Alzheimer's Disease via BDNF/CREB Signaling Pathway.

Transient receptor potential vanilloid 1 (TRPV1) protein is a Ca2+-permeable non-selective cation channel known for its pain modulation pathway. In a previous study, it was discovered that a triple-transgenic Alzheimer's disease (AD) mouse model (3xTg-AD+/+) has anti-AD effects. The expression of proteins in the brain-derived neurotrophic factor (BDNF)/cAMP response element binding protein (CREB) pathway in a 3xTg-AD/TRPV1 transgenic mice model was investigated to better understand the AD regulatory effect of TRPV1 deficiency. The results show that TRPV1 deficiency leads to CREB activation by increasing BDNF levels and promoting phosphorylation of tyrosine receptor kinase B (TrkB), extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and CREB in the hippocampus. Additionally, TRPV1 deficiency-induced CREB activation increases the antiapoptotic factor B-cell lymphoma 2 (Bcl-2) gene, which consequently downregulates Bcl-2-associated X (Bax) expression and decreases cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP), which leads to the prevention of hippocampal apoptosis. In conclusion, TRPV1 deficiency exhibits neuroprotective effects by preventing apoptosis through the BDNF/CREB signal transduction pathway in the hippocampus of 3xTg-AD mice.

Efficacy of Salvage Treatments in Relapsed or Refractory Diffuse Large B-Cell Lymphoma Including Chimeric Antigen Receptor T-Cell Therapy: A Systematic Review and Meta-Analysis.

PURPOSE: We intend to evaluate the efficacy of salvage treatments for relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) through meta-analysis. Materials and Methods: R/R DLBCL trials were divided into two groups based on eligibility for autologous stem-cell transplantation (ASCT), and meta-analysis of each group was performed. Random effects models were used to estimate the 1-year progression-free survival (PFS) rate, and chimeric antigen receptor (CAR) T-cell therapy was used as reference treatment. RESULTS: Twenty-six ASCT-eligible cohorts from 17 studies comprising 2,924 patients and 59 ASCT-ineligible cohorts from 53 studies comprising 3,617 patients were included in the pooled analysis. In the ASCT-eligible group, the pooled 1-year PFS rate was 0.40 (95% confidence interval [CI], 0.15 to 0.65) for the CAR T-cell group and 0.34 (95% CI, 0.30 to 0.37) for the group with chemotherapy followed by ASCT intention. The two treatments were not significantly different in meta-regression analysis. In the ASCT-ineligible group, the pooled 1-year PFS was 0.40 (95% CI, 0.35 to 0.46) for CAR T-cell, and the highest primary outcome was 0.47 (95% CI, 0.37 to 0.57) for the tafasitamab group. CAR T-cell therapy showed significantly better outcomes than chemotherapy and therapies based on ibrutinib, lenalidomide, and selinexor. However, loncastuximab, polatuzumab plus bendamustine and rituximab, and the tafasitamab group showed no different efficacy than CAR T-cell therapy after adjusting for median number of previous lines of treatment. CONCLUSION: Although several regimens were crudely grouped for classification, CAR T-cell therapy did not outperform chemotherapy followed by ASCT in the second-line setting or several recently developed agents in the ASCT-ineligible setting.

Synergistic therapeutic combination with a CAF inhibitor enhances CAR-NK-mediated cytotoxicity via reduction of CAF-released IL-6.

BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) contribute to an impaired functionality of natural killer (NK) cells that have emerged as a promising therapeutic modality. The interaction between CAFs and NK cells within the TME exerts major inhibitory effects on immune responses, indicating CAF-targeted therapies as potential targets for effective NK-mediated cancer killing. METHODS: To overcome CAF-induced NK dysfunction, we selected an antifibrotic drug, nintedanib, for synergistic therapeutic combination. To evaluate synergistic therapeutic efficacy, we established an in vitro 3D Capan2/patient-derived CAF spheroid model or in vivo mixed Capan2/CAF tumor xenograft model. The molecular mechanism of NK-mediated synergistic therapeutic combination with nintedanib was revealed through in vitro experiments. In vivo therapeutic combination efficacy was subsequently evaluated. Additionally, the expression score of target proteins was measured in patient-derived tumor sections by the immunohistochemical method. RESULTS: Nintedanib blocked the platelet-derived growth factor receptor ß (PDGFRß) signaling pathway and diminished the activation and growth of CAFs, markedly reducing CAF-secreted IL-6. Moreover, coadministration of nintedanib improved the mesothelin (MSLN) targeting chimeric antigen receptor-NK-mediated tumor killing abilities in CAF/tumor spheroids or a xenograft model. The synergistic combination resulted in intense NK infiltration in vivo. Nintedanib alone exerted no effects, whereas blockade of IL-6 trans-signaling ameliorated the function of NK cells. The combination of the expression of MSLN and the PDGFRß+-CAF population area, a potential prognostic/therapeutic marker, was associated with inferior clinical outcomes. CONCLUSION: Our strategy against PDGFRß+-CAF-containing pancreatic cancer allows improvements in the therapy of pancreatic ductal adenocarcinoma.

Advances in Nanozymes as a Paradigm for Viral Diagnostics and Therapy.

Over the past few decades, humankind has constantly encountered new viral species that create havoc in the socioeconomic balance worldwide. Among the method to combat these novel viral infections, fast and point-of-care diagnosis is of prime importance to contain the spreading of viral infections. However, most sensitive diagnostic systems for viral infections are time-consuming and require well-trained professionals, making it difficult for the patients. In recent years nanozymes emerged as promising therapeutic and fast diagnostic tools due to their multienzyme-like catalytic performance. Nanozymes can be designed using inorganic or organic components with tailorable physicochemical surface properties, enabling the attachment of various molecules and species on the surface of the nanozyme for specific recognition. In addition to the composition, the multienzyme-like catalytic performance can be modulated by the shape and size of the nanoparticles. Due to their multicatalytic abilities, nanozymes can be used for fast diagnosis and therapy for viral infections. Here we attempt to focus on the insights and recent explorations on the advances in designing various types of nanozymes as a theranostic tool for viral infections. Thus, this review intends to generate interest in the clinical translation of nanozymes as a theranostic tool for viral infections by providing knowledge about the multidisciplinary potential of nanozyme. SIGNIFICANCE STATEMENT: The multienzyme-like properties of nanozymes suggest their role in diagnosing and treating various diseases. Although the potential roles of nanozymes for various viral infections have been studied in the last few decades, no review provides recent explorations on designing various types of nanozymes for the detection and treatment of viral infections. This review provides insights into designing nanozymes to diagnose and treat viral infections, assisting future researchers in developing clinically translatable nanozymes to combat novel viral infections.

Temperature and oxidation-sensitive dioleoylphosphatidylethanolamine liposome stabilized with poly(ethyleneimine)/(phenylthio)acetic acid ion pair.

Temperature and oxidation-sensitive liposomes were prepared by stabilizing dioleoylphosphatidylethanolamine (DOPE) bilayers with the ion pair of poly(ethyleneimine)/(phenylthio)acetic acid (PEI/PTA). An upper critical solution temperature (UCST) behavior was observed when PEI/PTA ion pair was suspended in an aqueous solution. It was observed that the UCST increased with increasing PTA content. The ion pair was self-assembled into nanospheres owing to its amphiphilic property which was confirmed by transmission electron microscopy. The FT-IR spectroscopic spectrum showed that the ion pair formed a salt bridge between the amino group and the carboxyl group and the PTA content in the ion pair was readily oxidized by H2O2. Further, DOPE liposomal membranes could be stabilized with PEI/PTA ion pair. Due to the amphiphilic property, the ion pair played a role as a stabilizer for the formation of DOPE liposomes. The liposome released its payload in a temperature-responsive manner, possibly because when the temperature is raised, the ion pair loses its amphiphilic property and can be detached from the liposomal membrane. The liposome was also oxidation-responsive in terms of release, possibly because the amphiphilic property of the ion pair disappears when the PTA is oxidized.

Aruncus dioicus var. kamtschaticus Extract Ameliorates Psoriasis-like Skin Inflammation via Akt/mTOR and JAK2/STAT3 Signaling Pathways in a Murine Model.

Goat's beard (Aruncus dioicus var. kamtschaticus) is a traditional medicinal plant, widely used in Chinese and Korean traditional medicine because of its anti-inflammatory, anti-oxidant, antimicrobial, and anti-cancer activity. However, its effect on skin inflammatory diseases like psoriasis is unknown. The aim of this study was to investigate the therapeutic potency of A. dioicus extract (ADE) in in vitro and in vivo psoriasis models. ADE treatment significantly attenuated skin inflammation and improved skin integrity in imiquimod-treated mice by suppressing keratinocyte hyperproliferation, inhibiting the infiltration of immune cells, and downregulating the expression of psoriatic markers. Further, ADE treatment suppressed protein kinase B/mammalian target of rapamycin (Akt/mTOR) and Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) signaling in HaCaT cells. Overall, the application of ADE relieves psoriasis-like skin inflammation possibly by regulating the Akt/mTOR and JAK2/STAT3 signaling pathways, making it an effective alternative for psoriasis therapy.