Search

Purpose: To evaluate a new cultivated coral graft (CCG) in an in vivo experimental guided bone regeneration (GBR) procedure. Materials and Methods: The calvarias of eight rabbits were surgically exposed, and circular defects 8 mm in diameter were prepared. One defect was filled with CCG particles (experimental group); the contralateral defect (control group) was spontaneously filled by blood clot. All defects were covered with a collagen membrane. Subjects were euthanized after 8 weeks. Results: Histologic observations of the defects showed similar bone growth patterns in both experimental and control osteotomies. In the experimental defects, no traces of coral particles were observed. Histometric analysis showed denser bone in the pristine zone (65%-66%) than in the peripheral zone for both the control (50%) and experimental defects (31%) (P = not significant). The new bone percentage was reduced from the peripheral zone toward the middle and the center of the defect (31%, 32%, and 27%, respectively) as the distance from the peripheral pristine bone borders increased. Conclusions: The existing data supports the complete degradation of CCG as a space-maintaining scaffold for GBR procedures. [ABSTRACT FROM AUTHOR]

Postural assessments of the lumbar spine lack valuable information about its properties. The purpose of this study was to assess neutral zone (NZ) characteristics via in vivo lumbar spine passive stiffness and relate NZ characteristics to standing lumbar lordosis. A comparison was made between those that develop low back pain during prolonged standing (pain developers) and those that do not (nonpain developers). Twenty-two participants with known pain status stood on level ground, and median lumbar lordosis angle was calculated. Participants were then placed in a near-frictionless jig to characterize their passive stiffness curve and location of their NZ. Overall, both pain developers and nonpain developers stood with a lumbar lordosis angle that was more extended than their NZ boundary. Pain developers stood slightly more extended (in comparison to nonpain developers) and had a lower moment corresponding to the location of their extension NZ boundary. Overall, in comparison to nonpain developers, pain developers displayed a lower moment corresponding to the location of their extension NZ boundary which could correspond to greater laxity in the lumbar spine. This may indicate why pain developers have a tendency to stand further beyond their NZ with greater muscle co-contraction. [ABSTRACT FROM AUTHOR]

This canine in vivo study assessed the effect of recombinant human platelet-derived growth factor (rhPDGF) on the healing of periapical tissues following apical surgery. From a total of 96 premolar teeth, 64 teeth from six beagle dogs (2 years old) were classified as experimental and were randomly assigned to four experimental groups (16 teeth per group). After having the pulp extirpated, leaving teeth open to the oral cavity for 1 week, and sealing with an immediate restorative material for 8 weeks, nonsurgical endodontic treatment was performed. A split-mouth design was used, and intra-animal randomization of treatment sides was applied to the groups as follows: apical curettage + 1.5-mm root-end resection (Group 1); apicoectomy + mineral trioxide aggregate (MTA) root-end filling (Group 2); apicoectomy + MTA root-end filling + rhPDGF (Group 3); and apical curettage + rhPDGF (Group 4). The animals were sacrificed 24 months after apical surgery, and histologic and µCT analyses were performed for bone volume loss (BVL). Group 1 showed partial resolution of the periapical lesions without signs of tissue regeneration (BVL: 49.09 ± 10.97 mm3). Group 2 had minimal bone regeneration and showed cementum reformation in 9 teeth, with no direct attachment to the MTA (BVL: 35.34 ± 10.97 mm3). Group 3 showed regeneration of all damaged apical tissues without direct contact between the cementum and MTA (BLV: 4.51 ± 1.55 mm3). Group 4 showed regeneration of PDL, bone, and cementum and attachment of functional cementum fibers (BVL: 2.82 ± 2.3 mm3). The difference in BVL was statistically significant only for Groups 1 and 2 (P < .05). rhPDGF may help regenerate apical tissue structures following apical surgery. [ABSTRACT FROM AUTHOR]

One of the emerging non-digestible oligosaccharide prebiotics is β-mannooligosaccharides (β-MOS). β-MOS are β-mannan derived oligosaccharides, they are selectively fermented by gut microbiota, promoting the growth of beneficial microorganisms (probiotics), whereas the growth of enteric pathogens remains unaffected or gets inhibited in their presence, along with production of metabolites such as short-chain fatty acids. β-MOS also exhibit several other bioactive properties and health-promoting effects. Production of β-MOS using the enzymes such as β-mannanases is the most effective and eco-friendly approach. For the application of β-MOS on a large scale, their production needs to be standardized using low-cost substrates, efficient enzymes and optimization of the production conditions. Moreover, for their application, detailed in-vivo and clinical studies are required. For this, a thorough information of various studies in this regard is needed. The current review provides a comprehensive account of the enzymatic production of β-MOS along with an evaluation of their prebiotic and other bioactive properties. Their characterization, structural-functional relationship and in-vivo studies have also been summarized. Research gaps and future prospects have also been discussed, which will help in conducting further research for the commercialization of β-MOS as prebiotics, functional food ingredients and therapeutic agents. [ABSTRACT FROM AUTHOR]

In-vitro protein refolding is a major bottleneck step in the large-scale manufacturing of antibody fragments expressed in a microbial host system. The formation of an inter-chain disulfide bond is a key rate-limiting step during in-vitro refolding of antibody fragment therapeutics. In this investigation, we report the use of two redox mutant strains of E. coli viz., SHuffle® T7 (DE3) and SHuffle® T7 Express (DE3) possessing an oxidizing cytoplasm for the soluble expression of a refolded biosimilar antibody fragment. The effect of various critical process parameters on antibody fragment refolding yield was studied using a Design of Experiment (DoE) approach. The optimized upstream processing led to the expression of 167 ± 2.53 mg/L and 95 ± 1.44 mg/L of soluble refolded biosimilar Ranibizumab using the SHuffle® T7 (DE3) and SHuffle® T7 Express (DE3) strains, respectively, at the bioreactor scale. Physicochemical characteristics of the in-vivo refolded antibody fragment were studied and compared with an innovator molecule using various orthogonal analytical methods. A biological activity study of in-vivo refolded Ranibizumab using HUVEC cell-based bioassay proved that cell proliferation inhibition is comparable to the innovator Ranibizumab. The proposed strategy offers a time and cost-effective manufacturing platform for antibody fragments. [Display omitted] • Efficient soluble expression of in-vivo refolded antibody fragment. • Elimination of in-vitro refolding step. • DoE-based optimization of process parameters to enhance soluble target protein yield. • Novel downstream processing platform for the purification of antibody fragments. • Reduction in overall manufacturing time from nine days to three days. [ABSTRACT FROM AUTHOR]

The current study aimed to evaluate the pharmacokinetics and neuroprotective effect of well-characterised berberine-bovine serum albumin (BBR-BSA) nanoparticles. BBR-BSA nanoparticles were generated by desolvation method. Entrapment efficiency, loading capacity, particle size, polydispersity index, surface morphology, thermal stability, and in-vitro release were estimated. In-vitro pharmacokinetic and tissue distribution were conducted. Their neuroprotection was evaluated against lipopolysaccharides-induced neurodegeneration. BBR-BSA nanoparticles showed satisfactory particle size (202.60 ± 1.20 nm) and entrapment efficiency (57.00 ± 1.56%). Results confirmed the formation of spheroid-thermal stable nanoparticles with a sustained drug release over 48 h. Sublingual and intranasal routes had higher pharmacokinetic plasma profiles than other routes, with Cmax values at 0.75 h (444 ± 77.79 and 259 ± 42.41 ng/mL, respectively). BBR and its metabolite distribution in the liver and kidney were higher than in plasma. Intranasal and sublingual treatment improves antioxidants, proinflammatory, amyloidogenic biomarkers, and brain architecture, protecting the brain. In conclusion, neuroinflammation and neurodegeneration may be prevented by intranasal and sublingual BBR-BSA nanoparticles. [ABSTRACT FROM AUTHOR]

Papaya is one of the most consumed fruits around the world, which possesses low energy and is very suitable for those trying to reduce weight. Papaya is packed with a bunch of vitamins, minerals, as well as phenolic compounds. Phytochemicals have beneficial effects on the human body, including anti-cancer, anti-diabetic, and anti-dengue activities. Numerous studies have estimated nutritional and medicinal properties. The study of the bioaccessibility of papaya chemicals is important for both the food and medicine industries. This review summarizes the nutritional value and phytochemical content of different parts of papaya. Influencing factors like pre- and post-harvest on phytochemical content also have been reviewed. Further, the bioaccessibility and bioavailability of phytochemicals as well as the medicinal properties, based on the in vitro and in vivo studies are deeply reviewed. Finally, the research progress, gaps and interesting future aspects of papaya phytochemicals have been discussed. These phytochemical compounds are influenced by numerous factors, such as pre- and post-harvest, as well as extraction conditions. Many factors may affect the bioaccessibility and bioavailability of these phytochemicals, but there is limited information. Therefore, further studies like in vitro and in vivo experiments should be conducted to authenticate the efficiency of the papaya plant. [ABSTRACT FROM AUTHOR]

Despite the development of several anticancer treatments, there remains a need for new drugs that can overcome resistance and reduce side effects. While the medicinal herb Hydrocotyle umbellata (H. umbellata) has been used to relieve pain and inflammation, its antitumor properties have not yet been explored. In this study, we investigated the anticarcinogenic potential of H. umbellata extract (HUE) and its major components, as well as the underlying molecular mechanisms. Our results showed that HUE inhibited the growth of various tumor cell lines, including B16F10, without affecting non-cancer cells. Furthermore, HUE was effective in treating and preventing tumor growth in mice. Our mechanistic studies revealed that HUE inhibited cellular respiration, thereby reducing tumor cell proliferation. When combined with 2-deoxy-D-glucose, HUE demonstrated an enhanced anticancer effect by increasing the rate apoptosis. Analysis of the ethyl acetate and n-butanol fractions of HUE identified 1,3,4-trihydroxy-2-butanyl-α-d-glucopyranoside and caffeoylquinic acid derivatives as the major components responsible for the observed anticancer effects. In conclusion, our findings suggest that HUE and its two major components have the potential to be developed as effective therapeutic agents for a wide range of tumors by targeting cancer cell metabolism. [ABSTRACT FROM AUTHOR]

Vitreous, one of the largest components of the human eye, mostly contains water. Despite decades of studying the vitreous structure, numerous unanswered questions still remain, fueling ongoing active research. We attempt to provide a comprehensive overview of the current understanding of the development, morphology, biochemical composition, and function of the vitreous. We emphasize the impact of the vitreous structure and composition on the distribution of drugs. Fast-developing imaging technologies, such as modern optical coherence tomography, unlocked multiple new approaches, offering the potential for in vivo study of the vitreous structure. They allowed to analyze in vivo a range of vitreous structures, such as posterior precortical vitreous pockets, Cloquet canal, channels that interconnect them, perivascular vitreous fissures, and cisterns. We provide an overview of such imaging techniques and their principles and of some challenges in visualizing vitreous structures. Finally, we explores the potential of combining the latest technologies and machine learning to enhance our understanding of vitreous structures. [ABSTRACT FROM AUTHOR]

Proton MRS is used clinically to collect localized, quantitative metabolic data from living tissues. However, the presence of baselines in the spectra complicates accurate MRS data quantification. The occurrence of baselines is not specific to short‐echo‐time MRS data. In short‐echo‐time MRS, the baseline consists typically of a dominating macromolecular (MM) part, and can, depending on B0 shimming, poor voxel placement, and/or localization sequences, also contain broad water and lipid resonance components, indicated by broad components (BCs). In long‐echo‐time MRS, the MM part is usually much smaller, but BCs may still be present. The sum of MM and BCs is denoted by the baseline. Many algorithms have been proposed over the years to tackle these artefacts. A first approach is to identify the baseline itself in a preprocessing step, and a second approach is to model the baseline in the quantification of the MRS data themselves. This paper gives an overview of baseline handling algorithms and also proposes a new algorithm for baseline correction. A subset of suitable baseline removal algorithms were tested on in vivo MRSI data (semi‐LASER at TE = 40 ms) and compared with the new algorithm. The baselines in all datasets were removed using the different methods and subsequently fitted using spectrIm‐QMRS with a TDFDFit fitting model that contained only a metabolite basis set and lacked a baseline model. The same spectra were also fitted using a spectrIm‐QMRS model that explicitly models the metabolites and the baseline of the spectrum. The quantification results of the latter quantification were regarded as ground truth. The fit quality number (FQN) was used to assess baseline removal effectiveness, and correlations between metabolite peak areas and ground truth models were also examined. The results show a competitive performance of our new proposed algorithm, underscoring its automatic approach and efficiency. Nevertheless, none of the tested baseline correction methods achieved FQNs as good as the ground truth model. All separately applied baseline correction methods introduce a bias in the observed metabolite peak areas. We conclude that all baseline correction methods tested, when applied as a separate preprocessing step, yield poorer FQNs and biased quantification results. While they may enhance visual display, they are not advisable for use before spectral fitting. [ABSTRACT FROM AUTHOR]

Purpose: T 2$$ {}_2 $$‐weighted turbo‐spin‐echo (TSE) sequences are a fundamental technique in brain imaging but suffer from field inhomogeneities at ultra‐high fields. Several methods have been proposed to mitigate the problem, but were limited so far to nonselective three‐dimensional (3D) measurements, making short acquisitions difficult to achieve when targeting very high resolution images, or needed additional calibration procedures, thus complicating their application. Methods: Slab‐selective excitation pulses were designed for flexible placement utilizing the concept of k T$$ {}_T $$‐spokes. Phase‐coherent refocusing universal pulses were subsequently optimized with the Gradient Ascent Pulse Engineering algorithm and tested in vivo for improved signal homogeneity. Results: Implemented within a 3D variable flip angle TSE sequence, these pulses led to a signal‐to‐noise ratio (SNR) improvement ranging from 10% to 30% compared to a two‐dimensional (2D) T2w TSE sequence employing B1+$$ {\mathrm{B}}_1^{+} $$‐shimmed pulses. B1+$$ {\mathrm{B}}_1^{+} $$ field inhomogeneities could be mitigated and artifacts from B0$$ {\mathrm{B}}_0 $$ deviations reduced. The concept of universal pulses was successfully applied. Conclusion: We present a pulse design method which provides a set of calibration‐free universal pulses (UPs) for slab‐selective excitation and phase‐coherent refocusing in slab‐selective TSE sequences. [ABSTRACT FROM AUTHOR]

Olive family (Oleaceae) contains several species among which Olea europaea L. is mostly used for production of olive oils. Various parts of olive tree are rich source of diverse bioactive compounds such as Apigenin, elenolic acid, Hydroxytyrosol, Ligstroside, Oleoside, Oleuropein, Oleuropein aglycone, Tyrosol, etc. Among these, oleuropein, a secoiridoid is predominantly found in olive leaves and young olive fruits of different species of Oleaceae family. Scientists have adopted numerous extraction methods (conventional & latest) to increase the yield of oleuropein. Among these techniques, maceration, soxhlet, microwave-assisted, ultrasonication, and supercritical fluid methods are most commonly employed for extraction of oleuropein. Evidently, this review emphasizes on various in-vitro and in-vivo studies focusing on nutraceutical properties of oleuropein. Available literature highlights the pharmaceutical potential of oleuropein against various diseases such as obesity, diabetes, cardiovascular complications, neurodegenerative diseases, cancer, inflammation, microbial infections, and oxidation. This review will benefit the scientific community as it narrates comprehensive literature regarding absorption, metabolism, bioavailability, extraction techniques, and nutraceutical perspectives associated with oleuropein. [ABSTRACT FROM AUTHOR]

Repair of the damaged meniscus is a scientific challenge owing to the poor self-healing potential of the white area of the meniscus. Tissue engineering provides a new method for the repair of meniscus injuries. In this study, we explored the superiority of 2% hyaluronic acid chitin hydrogel in temperature sensitivity, in vitro degradation, biocompatibility, cell adhesion, and other biological characteristics, and investigated the advantages of hyaluronic acid (HA) and Transforming Growth Factor β1 (TGF-β1) in promoting cell proliferation and a matrix formation phenotype. The hydrogel loaded with HA and TGF-β1 promoted cell proliferation. The HA + TGF-β1 mixed group showed the highest glycosaminoglycan (GAG) content and promoted cell migration. Hydroxypropyl chitin (HPCH), HA, and TGF-β1 were combined to form a composite hydrogel with a concentration of 2% after physical cross-linking, and this was injected into a rabbit model of a meniscus full-thickness tear. After 12 weeks of implantation, the TGF-β1 + HA/HPCH composite hydrogel was significantly better than HPCH, HA/HPCH, TGF-β1 + HPCH, and the control group in promoting meniscus repair. In addition, the new meniscus tissue of the TGF-β1 + HA/HPCH composite hydrogel had a tissue structure and biochemical content similar to that of the normal meniscus tissue. [ABSTRACT FROM AUTHOR]

Background: Epilepsy, a common neurological disorder, has been increasingly associated with neuroinflammation, especially microglia activation. To gain insights into the research trends and patterns in this intersection, we conducted a bibliometric analysis of studies published between 2005 and 2024. Using the Web of Science Core Collection, we identified 1,229 relevant articles and reviews, focusing on the relationship between epilepsy and microglia. Methods: We employed the Bibliometrix R package and VOSviewer to analyze the data. Our search strategy combined epilepsy-related terms with microglia and microglial cell keywords. The analysis encompassed publication trends, country and institutional contributions, journal sources, authors, keywords, and thematic evolution. Results: The number of publications has steadily increased, particularly after 2019, indicating growing research interest. The United States, China, and Germany emerged as the most productive countries, with extensive collaboration between China and the United States. Epilepsia and Journal of Neuroinflammation were the most influential journals. Aronica E, Vezzani A, and Engel T were the most prolific authors. Thematic analysis revealed clusters focused on temporal lobe epilepsy, epilepsy-related disorders, and microglia activation. Over the past several years, research has shifted from fundamental brain function studies to in-vivo investigations of specific molecular mechanisms. The CSTB (-) mouse model and NF-κB signaling pathway both merit further in-depth investigation. Conclusion: In conclusion, this bibliometric study reveals a surge in epilepsymicroglia research, led by key countries, journals, and researchers. Temporal lobe epilepsy, epilepsy-related disorders, and microglia activation are focal themes. Future directions include exploring microglia activation mechanisms, utilizing animal models, and interdisciplinary approaches. [ABSTRACT FROM AUTHOR]

Purpose: We present a probabilistic approach to medical image analysis that requires, and makes use of, explicit prior information provided by a medical expert. Depending on the choice of prior model the method can be used for image enhancement, analysis, and segmentation. Methods: The methodology is based on a probabilistic approach to medical image analysis, that allows integration of 1) arbitrarily complex prior information (for which realizations can be generated), 2) information about a convolution operator of the imaging system, and 3) information about the noise in the reconstructed image into a posterior probability density. The method was demonstrated on positron emission tomography (PET) images obtained from a phantom and a patient with lung cancer. The likelihood model (multivariate log-normal) and the convolution operator were derived from phantom data. Two examples of prior information were used to show the potential of the method. The extended Metropolis-Hastings algorithm, a Markov chain Monte Carlo method, was used to generate realizations of the posterior distribution of the tracer activity concentration. Results: A set of realizations from the posterior was used as the base of a quantitative PET image analysis. The mean and variance of activity concentrations were computed, as well as the probability of high tracer uptake and statistics on the size and activity concentration of high uptake regions. For both phantom and in vivo images, the estimated images of mean activity concentrations appeared to have reduced noise levels, and a sharper outline of high activity regions, as compared to the original PET. The estimated variance of activity concentrations was high at the edges of high activity regions. Conclusions: The methodology provides a probabilistic approach for medical image analysis that explicitly takes into account medical expert knowledge as prior information. The presented first results indicate the potential of the method to improve the detection of small lesions. The methodology allows for a probabilistic measure of the size and activity level of high uptake regions, with possible long-term perspectives for early detection of cancer, aswell as treatment, planning, and follow-up. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common neurodegenerative disease, with an increasing prevalence. Currently, there is no ideal diagnostic molecular imaging agent for diagnosing AD. Antibodies (Abs) have been proposed to close this gap as they can bind selectively and with high affinity to amyloid β (Aβ)--one of the molecular hallmarks of AD. Abs can even be designed to selectively bind Aβ oligomers or isoforms, which are difficult to target with small imaging agents. Conventionally, Abs must be labeled with long-lived radionuclides which typically results in in high radiation burden to healthy tissue. Pretargeted imaging could solve this challenge as it allows for the use of short-lived radionuclides. To develop pretargeted imaging tools that can enter the brain, AD mouse models are useful as they allow testing of the imaging approach in a relevant animal model that could predict its clinical applicability. Several mouse models for AD have been developed with different characteristics. Commonly used models are: 5xFAD, APP/PS1 and tg-ArcSwe transgenic mice. In this study, we aimed to identify which of these models were best suited to investigate pretargeted imaging approaches beyond the blood brain barrier. We evaluated this by pretargeted autoradiography using the Aβ-targeting antibody 3D6 and an 111In-labeled Tz. Evaluation criteria were target-to-background ratios and accessibility. APP/PS1 mice showed Aβ accumulation in high and low binding brain regions and is as such less suitable for pretargeted purposes. 5xFAD and tg-ArcSwe mice showed similar uptake in high binding regions whereas low uptake in low binding regions and are better suited to evaluate pretargeted imaging approaches. 5xFAD mice are advantaged over tg-ArcSwe mice as pathology can be traced early (6 months compared to 18 months of age) and as 5xFAD mice are commercially available. [ABSTRACT FROM AUTHOR]

Vitamin A is essential for poultry health, influencing vision, growth, antioxidant defense, reproduction, and immune function. However, it is highly sensitive to degradation when exposed to light, moisture, heat, and oxygen. To address this, vitamin A is typically formulated as retinyl acetate in small beadlets. These beadlets are commonly included in premixes for industrial poultry diets. However, variations in beadlet formulations among different producers can lead to differences in stability and bioavailability, potentially impacting their effectiveness and biological value for poultry. Understanding the stability and bioavailability of various vitamin A sources is crucial for optimizing poultry feeding strategies and ensuring adequate vitamin A supply. The stability of vitamin A can be evaluated through several methods, including premix stability, stability during pelleting, storage stability in feed, and the stability of pure vitamin A products. Bioavailability, which reflects how effectively vitamin A is absorbed and utilized by the animal, is typically assessed through in vivo studies, with liver retinol levels serving as a key indicator. To enhance poultry production, it is important to select vitamin A sources that offer both high stability and bioavailability. Effective feed management, including the use of stable and readily absorbed forms of vitamin A, can improve poultry health, growth rates, and overall production efficiency. [ABSTRACT FROM AUTHOR]

Single-photon emission computed tomography (SPECT) systems with pinhole collimators are becoming increasingly important in clinical and preclinical nuclear medicine investigations as they can provide a superior resolution-sensitivity tradeoff compared to conventional parallel-hole and fanbeam collimators. Previously, open-source software did not exist for reconstructing tomographic images from pinhole-SPECT datasets. A 3D SPECT system matrix modelling library specific for pinhole collimators has recently been integrated into STIR, an open-source software package for tomographic image reconstruction. The pinhole-SPECT library enables corrections for attenuation and the spatially variant collimator-detector response by incorporating their effects into the system matrix. Attenuation correction can be calculated with a simple single line of response or a full model. The spatially variant collimator-detector response can be modelled with a point spread function and depth of interaction corrections for increased system matrix accuracy. In addition, improvements to computational speed and memory requirements can be made with image masking. This work demonstrates the flexibility and accuracy of STIR's support for pinhole-SPECT datasets using measured and simulated single-pinhole SPECT data from which reconstructed images were analysed quantitatively and qualitatively. The extension of the opensource STIR project with advanced pinhole-SPECT modelling will enable the research community to study the impact of pinhole collimators in several SPECT imaging scenarios and with different scanners. [ABSTRACT FROM AUTHOR]

Background: For glioma patients, the long-term advantages of dendritic cells (DCs) immunization remain unknown. It is extremely important to develop new treatment strategies that enhance the immunotherapy effect of DC-based vaccines. DCs exposed to glioma stem cells (GSCs) are considered promising vaccines against glioma. Methods: Glioma stem cells were isolated from mouse glioma GL261 cells (GCs). Both were subjected to severe (47°C) and mild (42°C) heat shock to induce immunogenic cell death (ICD). Membrane mobilization of calreticulin (CRT) and release of heat shock proteins (HSPs) were detected by flow cytometry. Dendritic cells were then exposed to heat-inactivated cells and co-culturing of T cells tested for immunotherapeutic efficacy in vitro. In vivo, we investigated the GSC targeting effect of the GSC-DC vaccine combined with CD47 blockade. Results: Heat shock induced ICD in GCs and GSCs, as indicated by significant release of calreticulin, HSP70, and HSP90. Heat shock condition ICD lysates induce maturation and activation-associated marker expression on monocyte-derived DCs. Accordingly, DCs pulsed with GCs and GSCs inactivated reduced colony formation, sphere formation, migration, and invasion of glioma and GSCs in vitro. Glioma stem cell-DC vaccine in combination with anti-CD47 antibody significantly enhanced survival in mice with glioma, induced production of interferon (IFN)-γ, and enhanced T-cell expansion in vivo. Of note, DCs pulsed with inactivated GSCs were more effective to control tumor growth than DCs pulsed with inactive GCs. Conclusions: Severe heat shock induces ICD in vitro. These data showed that administration of anti-CD47 antibody combined with GSC-DC vaccine may represent an effective immunotherapeutic strategy for cancer patients in clinical. [ABSTRACT FROM AUTHOR]

Background: Bone grafts are extensively used for repairing bone defects and voids in orthopedics and dentistry. Moldable bone grafts offer a promising solution for treating irregular bone defects, which are often difficult to fill with traditional rigid grafts. However, practical applications have been limited by insufficient mechanical strength and rapid degradation. Methods: This study developed a ceramic composite bone graft composed of calcium sulfate (CS), β-tricalcium phosphate (β-TCP) with/without graphene oxide (GO) nano-particles. The biomechanical properties, degradation rate, and in-vitro cellular responses were investigated. In addition, the graft was implanted in-vivo in a critical-sized calvarial defect model. Results: The results showed that the compressive strength significantly improved by 135% and the degradation rate slowed by 25.5% in comparison to the control model. The addition of GO nanoparticles also improved cell compatibility and promoted osteogenic differentiation in the in-vitro cell culture study and was found to be effective at promoting bone repair in the in-vivo animal model. Conclusions: The mixed ceramic composites presented in this study can be considered as a promising alternative for bone graft applications. [ABSTRACT FROM AUTHOR]

Our previous research revealed a close association between the acetylation of peroxisome proliferator-activated receptor γ (PPARγ) histone H3K27 and the adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). We preliminarily explored the epigenetic mechanism of steroid-induced avascular necrosis of the femoral head (SANFH) development, but the specific histone deacetylase (HDAC) involved in this regulatory process remains unknown. In this study, we combined cell, animal, and clinical specimen experiments to screen for specific HDAC genes that could regulate BMSC adipogenic differentiation and to explore their roles. The results showed that dexamethasone (DEX) significantly exacerbated the imbalance between the adipogenic and osteogenic differentiation of BMSCs, and there were differences in HDAC expression in the adipogenic differentiation cell models, with histone deacetylase 10 (HDAC10) showing the most significant decrease in expression. Subsequent use of a chromatin immunoprecipitation assay kit and quantitative polymerase chain reaction (ChIP‒qPCR) revealed a decrease in HDAC10 expression at predicted potential sites within the PPARγ promoter, indicating a significant decrease in HDAC10 enrichment in the PPARγ promoter region of BMSCs, thereby promoting sustained PPARγ expression. Additionally, immunohistochemistry of samples collected from mice and humans with SANFH and normal femoral heads revealed an imbalance between adipogenic and osteogenic differentiation in the necrotic area of femoral heads, with a significant decrease in the relative expression of HDAC10 in the necrotic area of femoral heads with SANFH. In summary, we speculate that HDAC10 affects the progression of SANFH by regulating BMSC adipogenic differentiation, a process possibly related to PPARγ histone acetylation. These findings provide a promising direction for the treatment of SANFH. [ABSTRACT FROM AUTHOR]

Background: Huanglianjiedu decoction (HLJDD) is a classical Traditional Chinese Medicine (TCM) prescription with thousand years of clinical use against various malignancies, including pancreatic adenocarcinoma (PAAD). However, its potential bioactive component and molecular mechanism remains unclear. Aims: This study is to inspect the HLJDD mechanisms of action against PAAD via integrated computational and pharmacochemistry strategy, in vivo and in vitro experiments to validate associated targets and pathways. Methods: A PAAD xenograft model was established by subcutaneous injecting Panc02 cells into C57BL/6 mice. Ultra-high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) was engaged to determine constituents of HLJDD and assessed for pharmacokinetic scheme using the TCM Systems Pharmacology Platform (TCM-SP). Differentially expressed genes (DEGs) of PAAD was retrieved from the transcriptome dataset GSE43795, followed by recognizing overlapping targets the oncogenes and target genes of PAAD and HLJDD, respectively. Putative signaling pathways of HLJDD in treating PAAD were enriched using KEGG and GO analyses. The anti-PAAD effects of HLJDD was assessed in vivo and in vitro, besides, the potential mechanism was validated using immunoblotting and immunohistochemical assays. Results: HLJDD significantly suppressed the growth of transplanted PAAD tumors, constrained PAAD progression, and induced apoptosis and S-phase arrest. Seventy-five active components meeting the drug-likeness criteria and 278 target genes of HLJDD were identified. KEGG analysis indicated that the top three enriched pathways were cancer, AGE-RAGE signaling, and IL-17 signaling pathways. Disease enrichment analysis highlighted immune, pharmacological, and cancer-related diseases as the top three categories. A total of 47 potential target genes were identified. Immunoblotting revealed that HLJDD inhibited PI3K and MAPK-related signaling pathways, while immunohistochemical staining confirmed that HLJDD suppressed the expression of phosphorylated MAPK and ERK1/2. Conclusion: HLJDD inhibited PAAD in vitro and in vivo via the modulation of multiple mechanisms, including regulation of PI3K/AKT/mTOR and MAPK/ERK1/2 signaling pathways. [ABSTRACT FROM AUTHOR]

This study aimed to design sustained released biodegradable calcium carbonate nanoparticles loaded with chlorhexidine (CHX-loaded NPs) and to investigate the early osteogenic differentiation and antimicrobial effects on the important bacteria involved in infections of dental implants. The microemulsion method was used to prepare the calcium carbonate nanoparticles loaded with chlorhexidine. The prepared nanoparticles were characterized using conventional methods. The release pattern determination and the biodegradation test were performed for the prepared nanoparticles. For the early osteogenic differentiation test of the prepared nanoparticles, alkaline phosphatase (ALP) activity was detected in human dental pulp stem cells (HDPSCs). The antimicrobial effects of the nanoparticles were evaluated against Escherichia coli, Streptococcus mutans, Enterococcus faecalis, Staphylococcus aureus, and Pseudomonas aeruginosa. The sizes of free calcium carbonate nanoparticles and CHX-loaded NPs were 105 ± 1.63 and 118 ± 1.47 nm and their zeta potentials were − 27 and − 36, respectively. A 50% degradation of nanoparticles was achieved after 100 days. These nanoparticles showed a two-stage sustained release pattern in vitro. Microscopic images revealed that the morphology of free calcium carbonate nanoparticles primarily took on a spherical calcite form, while CHX-loaded NPs predominantly exhibited a cauliflower-like vaterite polymorph. The nanoparticles increased the activity of ALP in cells in two weeks significantly (p < 0.05). Antimicrobial and antibiofilm results showed an efficient effect of the prepared nanoparticle against the studied bacteria. Calcium carbonate nanoparticles are an efficient multifunctional vector for chlorhexidine and can be used as a bioactive antibacterial agent against various oral microorganisms to prevent implant infections. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is widely recognized as a key factor in the pathogenesis of Alzheimer's disease (AD), alongside ß-amyloid deposition and the formation of neurofibrillary tangles. The NLR family pyrin domain containing 3 (NLRP3) inflammasome, part of the innate immune system, has been implicated in the neuropathology of both preclinical amyloid and tau transgenic models. Activation of the NLRP3 pathway involves an initial priming step, which increases the expression of Nlrp3 and interleukin (IL)-1ß, followed by the assembly of the NLRP3 inflammasome complex, comprising NLRP3, ASC, and caspase-1. This assembly leads to the proteolytic maturation of the pro-inflammatory cytokines IL-1ß and IL-18. Additionally, the NLRP3 inflammasome induces Gasdermin D (GSDMD) cleavage, forming membrane pores through which IL-1ß and IL-18 are secreted. Inhibition of NLRP3 has been shown to enhance plaque clearance by modulating microglial activation. Furthermore, blocking NLRP3 in tau transgenic mice has been found to reduce tau phosphorylation by affecting the activity of certain tau kinases and phosphatases. Methods: In this study, organotypic brain slice cultures from P301S transgenic mice were treated with lipopolysaccharide (LPS) plus nigericin as a positive control or exposed to tau seeds (K18) to evaluate NLRP3 inflammasome activation. The effect of tau seeding on NLRP3 activity was further examined using Meso Scale Discovery (MSD) assays to measure IL1ß secretion levels in the presence and absence of NLRP3 inhibitors. The role of NLRP3 activity was investigated in fullbody Nlrp3 knockout mice crossbred with the tau transgenic P301S model. Additionally, full-body and microglia-selective Gsdmd knockout mice were crossbred with P301S mice, and tau pathology and neurodegeneration were evaluated at early and late stages of the disease using immunohistochemistry and biochemical assays. Results: Activation of the NLRP3 pathway was observed in the mouse organotypic slice culture (OSC) model following stimulation with LPS and nigericin or exposure to tau seeds. However, Nlrp3 deficiency did not mitigate tauopathy or neurodegeneration in P301S mice in vivo, showing only a minor effect on plasma neurofilament (NF-L) levels. Consistently, Gsdmd deficiency did not alter tau pathology in P301S mice. Furthermore, neither full-body nor microglia-selective Gsdmd deletion had an impact on neuronal pathology or the release of pro-inflammatory cytokines. Conclusion: The absence of key components of the NLRP3 inflammasome pathway did not yield a beneficial effect on tau pathology or neurodegeneration in the preclinical Tau-P301S mouse model of AD. Nonetheless, organotypic slice cultures could serve as a valuable ex vivo mechanistic model for evaluating NLRP3 pathway activation and pharmacological inhibitors. [ABSTRACT FROM AUTHOR]

Though interferons (IFNs) were once heralded as panaceas to numerous diseases, how cells decode varying IFN stimuli and subsequently produce (in)appropriate signaling remain unclear. Our labs recently engineered novel erythropoietin receptor-IFN chimeric receptors, and we highlight their utility in two cases uncovering different ial genetic determinants of type I (IFN-α/β) and type III (IFN-λ) IFN signaling. These and other types of synthetic (cytokine) receptors could be expanded to real-time signaling dynamics and in vivo studies. [ABSTRACT FROM AUTHOR]

Aim: To identify an optimized strategy for the large‐scale production of nanovesicles (NVs) that preserve the biological properties of exosomes (EXOs) for use in periodontal regeneration. Materials and Methods: NVs from dental follicle stem cells (DFSCs) were prepared through extrusion, and EXOs from DFSCs were isolated. The yield of both extruded NVs (eNVs) and EXOs were quantified through protein concentration and particle number analyses. Their pro‐migration, pro‐proliferation and pro‐osteogenesis capacities were compared subsequently in vitro. Additionally, proteomics analysis was conducted. To further evaluate the periodontal regeneration potential of eNVs and EXOs, they were incorporated into collagen sponges and transplanted into periodontal defects in rats. In vivo imaging and H&E staining were utilized to verify their biodistribution and safety. Micro‐Computed Tomography analysis and histological staining were performed to examine the regeneration of periodontal tissues. Results: The yield of eNVs was nearly 40 times higher than that of EXOs. Interestingly, in vitro experiments indicated that the pro‐migration and pro‐proliferation abilities of eNVs were superior, and the pro‐osteogenesis potential was comparable to EXOs. More importantly, eNVs exhibited periodontal regenerative potential similar to that of EXOs. Conclusions: Extrusion has proven to be an efficient method for generating numerous eNVs with the potential to replace EXOs in periodontal regeneration. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a prevalent and disabling disease that affects a significant proportion of the global population. Urine-derived stem cells (USCs) have shown great prospects in the treatment of OA, but there is no study that has compared them with traditional stem cells. Purpose: This study aimed to compare the therapeutic efficacy and mechanisms of USCs and adipose-derived stem cells (ADSCs) for OA treatment. Study Design: Controlled laboratory study. Methods: We compared the biological properties of USCs and ADSCs using CCK-8, colony formation, EdU, adhesion, and apoptosis assays. We evaluated the protective effects of USCs and ADSCs on IL-1β–treated OA chondrocytes by chemical staining, immunofluorescence, and Western blotting. We assessed the effects of USCs and ADSCs on chondrocyte autophagy by transmission electron microscopy, immunofluorescence, and Western blotting. We also compared the therapeutic efficacy of intra-articular injections of USCs and ADSCs by gross, histological, micro–computed tomography, and immunohistochemical analyses in an OA rat model induced by anterior cruciate ligament transection. Results: USCs showed higher proliferation, colony formation, DNA synthesis, adhesion, and anti-apoptotic abilities than ADSCs. Both USCs and ADSCs increased the expression of cartilage-specific proteins and decreased the expression of matrix degradation–related proteins and inflammatory factors in OA chondrocytes. USCs had a greater advantage in suppressing MMP-13 and inflammatory factors than ADSCs. Both USCs and ADSCs enhanced autophagy in OA chondrocytes, with USCs being more effective than ADSCs. The autophagy inhibitor 3-MA reduced the enhanced autophagy and protective effects of USCs and ADSCs on OA chondrocytes. Conclusion: To our knowledge, this is the first study to explore the efficacy of USCs in the treatment of knee OA and to compare them with ADSCs. Considering the superior properties of USCs in terms of noninvasive acquisition, a high cost-benefit ratio, and low ethical concerns, our study suggests that they may be a more promising therapeutic option than ADSCs for OA treatment under rigorous regulatory pathways. Clinical Relevance: USCs may be a superior cell source for stem cells to treat knee OA, and this study strengthens the evidence for the application of USCs. [ABSTRACT FROM AUTHOR]

Background: Environmentally persistent free radicals (EPFRs) are generated in the combustion processes of solid waste and can cause adverse influences on human health, especially lung diseases. Lung cancer is one of the most serious malignancies in recent years, which the global deaths rate is about 1.6 million every year. Methods and Results: In this study, we verified that ZnO/MCB EPFRs promote cell proliferation and migration, impedes cell apoptosis in lung cancer. Furthermore, we found that ZnO/MCB could influence the expression of miRNAs (miR-18a and miR-34a). In vivo, ZnO/MCB and ZnO EPFRs can reduce the weight and survival rate of BALB/c male mice more than that of BALB/c female mice. In the ZnO/MCB exposed group, male mice lung became even smaller, while the female mice the lung increased significantly. Taken together, our results provide evidence for assessing the potential health risks of persistent free radicals on fine particles. Conclusions: This study linked toxicity of EPFRs with miRNAs revealed the potential health hazard to human lung cancer. [ABSTRACT FROM AUTHOR]

Background: Numerous studies have recorded the function of long noncoding RNAs (lncRNAs) in cancer development, including lung adenocarcinoma (LUAD). Previous studies have reported the crucial role of lncRNA PTPRG antisense RNA 1 (PTPRG-AS1) in various cancers. However, the role of PTPRG-AS1 in LUAD remains unknown. Materials and Methods: Real-time quantitative polymerase chain reaction (RT-qPCR) was applied for detecting PTPRG-AS1 expression in LUAD cell lines. Functional assays and in vivo experiments explored cell proliferation, whereas flow cytometry analysis was used to detect cell cycle. In addition, fluorescent in situ hybridization (FISH) and subcellular fractionation assay measured the localization of PTPRG-AS1 in LUAD cells. RNA pulldown, luciferase reporter, and RNA immunoprecipitation (RIP) assays were used to investigate the interaction of PTPRG-AS1/miR-124-3p/cyclin D1 (CCND1) axis. Results: PTPRG-AS1 expression was notably high in LUAD cell lines. PTPRG-AS1 knockdown suppressed cell proliferation and cycle as well as the level of CCND1. Moreover, miR-124-3p was the mutual target of PTPRG-AS1 and CCND1. In addition, PTPRG-AS1 sponged miR-124-3p to upregulate CCND1 in LUAD cells. Moreover, miR-124-3p depletion reversed the suppression of PTPRG-AS1 silence on LUAD cell behaviors, but then CCND1 knockdown countervailed the promoting influence of downregulated miR-124-3p. Conclusions: PTPRG-AS1 propels cell proliferation and cell cycle of LUAD by targeting miR-124-3p/CCND1 axis. [ABSTRACT FROM AUTHOR]

This study outlines the development of a cost-effective, extended-release febuxostat (FEB) tablet using activated charcoal as an adsorbent to enhance drug release. FEB, a BCS Class II drug, presents formulation challenges due to low solubility and high lipophilicity. We evaluated eight formulations with varying FEB-to-charcoal ratios using FTIR and DSC for physical interactions and followed USP standards for overall assessment. The optimal 1:0.25 FEB-to-charcoal ratio demonstrated a consistent 12 h zero-order release pattern. In vivo studies indicated a significantly extended plasma profile compared to immediate-release tablets. The optimal tablets demonstrated acceptable hardness and disintegration times. This innovative approach enhances patient compliance, improves bioavailability, and reduces production costs, offering a promising solution for controlled FEB delivery. [ABSTRACT FROM AUTHOR]

In recent years, injectable hydrogels and cardiac patches have provided a promising approach to improve cardiac regeneration and function after myocardial infarction, however, the crucial designing factors of these biomaterials have been less reviewed. Therefore, in this review, we speculate on the prominent design parameters. A profound understanding of the main properties of native heart tissue can guide the efforts to obtain biomaterials with desirable biomimicking properties that improve the effectiveness of future fabricated myocardial biomaterials. Moreover, the injectable hydrogels and cardiac patches with reactive oxygen species scavenging properties will be reviewed in detail owing to the promising results of in vitro and in vivo studies on cardiac regeneration after myocardial infarction. This review can pave the way for an optimized design for effective cardiac biomaterials by considering the optimum ranges for physical, chemical, and biological characteristics of biomaterials, as well as the study of undetected parameters that can be investigated in future studies. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer immunotherapy has evolved rapidly in the last decade. A newly emerging immunotherapeutic approach utilizes oncolytic viruses to enhance the ability of the body's own immune system to recognize and clear tumor cells. We have recently developed a novel chimeric oncolytic virus and demonstrated its anti-tumoral effects in various preclinical mouse models. To gain mechanistic insights into the immune response to this form of therapy at the cellular level and to identify targets to potentially further improve the therapy, we analyzed the immune cell signature in the tumors, blood, and lymphoid tissue in a syngeneic melanoma mouse model by flow cytometry. Both local and systemic immune responses were observed. Furthermore, selective depletion of cytotoxic T cells indicated that these cells are the main players in mediating the therapeutic response to this novel virotherapy. Background/Objectives: Oncolytic virotherapy is a promising approach in cancer immunotherapy. We have previously described a recombinant hybrid oncolytic virus (OV), VSV-NDV, which has a favorable safety profile and therapeutic immunogenicity, leading to direct oncolysis, abscopal effects, and prolonged survival in syngeneic in vivo tumor models. While OVs are known to mediate systemic anti-tumor immune responses, the detailed characterization of local and systemic immune responses to fusogenic oncolytic virotherapy remains unexplored. Methods and Results: We analyzed immune cell compartments in the spleen, blood, tumor-draining lymph nodes (TDLNs), and tumors over the course of VSV-NDV therapy in a bilateral syngeneic melanoma mouse model. Our results revealed significant local infiltration and activation of T lymphocytes in tumors and globally in the blood and spleen. Notably, in vivo CD8+ T cell depletion led to complete abrogation of the tumor response, highlighting the crucial role of T cells in promoting the therapeutic effects of oncolytic VSV-NDV. In vitro co-culture experiments enabled the interrogation of human immune cell responses to VSV-NDV-mediated oncolysis. Human peripheral blood mononuclear cells (PBMCs) were efficiently stimulated by exposure to VSV-NDV-infected cancer cells, which recapitulates the in vivo murine findings. Conclusions: Taken together, these data characterize a broad anti-tumor immune cell response to oncolytic VSV-NDV therapy and suggest that CD8+ T cells play a decisive role in therapeutic outcome, which supports the further development of this chimeric vector as a multimechanistic immunotherapy for solid cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is surrounded by a dense fibrotic environment due to the activity of pancreatic stellate cells (PSCs). This hinders the effectiveness of treatment by limiting drug penetration and oxygen delivery. To better understand this, PSCs and cancer cells were studied in laboratory models using radiotracer imaging techniques. The results indicated that while glucose uptake and hypoxia were similar between cancer cells alone and in combination with PSCs, a specific marker of fibrosis (FAPα) was significantly higher in PSC-rich environments. In mice, the marker in question decreased in tumors with only PSCs, indicating that the cells had died. Conversely, the biomarker increased over time in tumors containing both cancer cells and PSCs, suggesting that mouse cells had invaded. This study sheds light on how the tumor environment influences metabolism and thus provides insights for more targeted theranostic applications. In turn, this approach supports the development of more reliable models. Background/Objective Pancreatic stellate cells (PSCs) in pancreatic adenocarcinoma (PDAC) are producing extracellular matrix, which promotes the formation of a dense fibrotic microenvironment. This makes PDAC a highly heterogeneous tumor-stroma-driven entity, associated with reduced perfusion, limited oxygen supply, high interstitial fluid pressure, and limited bioavailability of therapeutic agents. Methods In this study, spheroid and tumor xenograft models of human PSCs and PanC-1 cells were characterized radiopharmacologically using a combined positron emission tomography (PET) radiotracer approach. [18F]FDG, [18F]FMISO, and [18F]FAPI-74 were employed to monitor metabolic activity, hypoxic metabolic state, and functional expression of fibroblast activation protein alpha (FAPα), a marker of activated PSCs. Results In vitro, PanC-1 and multi-cellular tumor spheroids demonstrated comparable glucose uptake and hypoxia, whereas FAPα expression was significantly higher in PSC spheroids. In vivo, glucose uptake as well as the transition to hypoxia were comparable in PanC-1 and multi-cellular xenograft models. In mice injected with PSCs, FAPα expression decreased over a period of four weeks post-injection, which was attributed to the successive death of PSCs. In contrast, FAPα expression increased in both PanC-1 and multi-cellular xenograft models over time due to invasion of mouse fibroblasts. Conclusion The presented models are suitable for subsequently characterizing stromal cell-induced metabolic changes in tumors using noninvasive molecular imaging techniques. [ABSTRACT FROM AUTHOR]

Simple Summary: Gastric cancer (GC) represents a major global health challenge, ranking as the second leading cause of cancer-related deaths. The high mortality rate is primarily due to late-stage diagnoses, which limit effective treatment options. Recent research emphasizes the development of targeted therapies and radiation immunotherapy as promising alternatives to traditional approaches. The review authors summarize recent advancements in targeted therapies for gastric cancer, focusing on both laboratory and clinical studies. They explore targeted approaches that have shown potential for improving diagnostic accuracy and treatment effectiveness. The findings of this paper may significantly impact the research community by highlighting the importance of personalized medicine in gastric cancer treatment. By identifying specific molecular targets and utilizing nanotechnology for drug delivery, these advancements aim to enhance treatment efficacy while minimizing systemic toxicity. Overall, the review suggests the potential for improved prognosis and treatment strategies through targeted therapies and precision medicine. Gastric cancer (GC) is the second most common cause of cancer-related death worldwide and a serious public health concern. This high death rate is mostly caused by late-stage diagnoses, which lead to poor treatment outcomes. Radiation immunotherapy and targeted therapies are becoming increasingly popular in GC treatment, in addition to surgery and systemic chemotherapy. In this review, we have focused on both in vitro and in vivo research, which presents a summary of recent developments in targeted therapies for gastric cancer. We explore targeted therapy approaches, including integrin receptors, HER2, Claudin 18, and glutathione-responsive systems. For instance, therapies targeting the integrin receptors such as the αvβ3 and αvβ5 integrins have shown promise in enhancing diagnostic precision and treatment efficacy. Furthermore, nanotechnology provides novel approaches to targeted drug delivery and imaging. These include glutathione-responsive nanoplatforms and cyclic RGD peptide-conjugated nanoparticles. These novel strategies seek to reduce systemic toxicity while increasing specificity and efficacy. To sum up, the review addresses the significance of personalized medicine and advancements in gastric cancer-targeted therapies. It explores potential methods for enhancing gastric cancer prognosis and treatment in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Change in protein expression is the key driving force for tumorigenesis. Increased expression of Ankyrin Repeat Domain 1 (ANKRD1) acts as a co-activator of the p53 tumor suppressor protein and is associated with cancer drug resistance and poor survival of cancer patients. In this study, we found increased levels of ANKRD1 in highly metastatic breast cancer cell lines and human tissues of high-grade breast cancer. We also demonstrated that ANKRD1 is upstream of NF-κB-MAGE-A6 and plays a role in cancer metastasis. Our results show that the expression of ANKRD1 has significant clinical diagnostic significance in breast cancer metastasis. Early detection and surgical excision of tumors have helped improve the survival rate of patients with breast cancer. However, patients with metastatic cancer typically have a poor prognosis. In this study, we propose that ANKRD1 promotes metastasis of breast cancer. ANKRD1 was found to be highly expressed in the MDA-MB-231 and MDA-LM-2 highly metastatic breast cancer cell lines compared to the non-metastatic breast cancer cell lines (MCF-7, ZR-75-30, T47D) and normal breast cancer cells (MCF-10A). Furthermore, high-grade tumors showed increased levels of ANKRD1 compared to low-grade tumors. Both in vitro and in vivo functional studies demonstrated the essential role of ANKRD1 in cancer cell migration and invasion. The previous studies have suggested a significant role of NF-κB and MAGE-A6 in breast cancer metastasis, but the upstream regulators of this axis are not well characterized. Our study suggests that ANKRD1 promotes metastasis of breast cancer by activating NF-κB as well as MAGE-A6 signaling. Our findings show that ANKRD1 is a potential therapeutic target and a diagnostic marker for breast cancer metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: DNA-dependent protein kinase (DNA-PK) is a key player in repairing DNA damage. Ku proteins detect DNA damage and activate DNA-PK. Blocking DNA-PK can make cancer treatments such as radiation more effective. We have developed Ku–DNA binding inhibitors (Ku-DBis) that stop DNA-PK activation, making cancer cells more sensitive to radiation. We recently discovered new Ku-DBis that enter cells better than predecessor compounds, allowing cellular and in vivo analyses. Some non-small cell lung cancer (NSCLC) cells, especially those lacking ATM, were very sensitive to these inhibitors and radiation. However, cells lacking BRCA1 were resistant, which reduced the effectiveness of radiation. In animal studies of NSCLC, Ku-DBi treatment inhibited DNA-PK and enhanced a radiation-dependent decrease in tumor cell proliferation. This is the first time a Ku-targeted inhibitor has been shown to work in living organisms, suggesting their potential application in cancer treatment. Background: DNA-dependent protein kinase (DNA-PK) is a validated cancer therapeutic target involved in DNA damage response (DDR) and non-homologous end-joining (NHEJ) repair of DNA double-strand breaks (DSBs). Ku serves as a sensor of DSBs by binding to DNA ends and activating DNA-PK. Inhibition of DNA-PK is a common strategy to block DSB repair and improve efficacy of ionizing radiation (IR) therapy and radiomimetic drug therapies. We have previously developed Ku–DNA binding inhibitors (Ku-DBis) that block in vitro and cellular NHEJ activity, abrogate DNA-PK autophosphorylation, and potentiate cellular sensitivity to IR. Results and Conclusions: Here we report the discovery of oxindole Ku-DBis with improved cellular uptake and retained potent Ku-inhibitory activity. Variable monotherapy activity was observed in a panel of non-small cell lung cancer (NSCLC) cell lines, with ATM-null cells being the most sensitive and showing synergy with IR. BRCA1-deficient cells were resistant to single-agent treatment and antagonistic when combined with DSB-generating therapies. In vivo studies in an NSCLC xenograft model demonstrated that the Ku-DBi treatment blocked IR-dependent DNA-PKcs autophosphorylation, modulated DDR, and reduced tumor cell proliferation. This represents the first in vivo demonstration of a Ku-targeted DNA-binding inhibitor impacting IR response and highlights the potential therapeutic utility of Ku-DBis for cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Xeroderma pigmentosum (XP) is a very rare recessive disease caused by the incapacity to resolve ultraviolet-induced DNA lesions through Nucleotide Excision Repair (NER). Some XP patients suffer from aggressive skin carcinoma and melanoma at a very early age (<8). Our previous results show that primary XP fibroblasts isolated from healthy, non-photo-exposed skin negatively impact the extracellular matrix and the activation of the innate immune system. Here, we show for the first time that XP group C primary fibroblasts also play a major role in cancer cell invasion ex vivo and in vivo through the overexpression of Hepatocyte Growth Factor/Scatter Factor (HGF/SF) in the absence of genotoxic attacks. Using inhibitors of the activation of the HGF/SF pathway counteracted the effects of XP fibroblasts on the growth of cancer cells, suggesting new perspectives in the care of XP patients. Xeroderma pigmentosum (XP) is a very rare recessive disease caused by the incapacity to resolve ultraviolet-induced DNA lesions through Nucleotide Excision Repair (NER). Most XP patients suffer from aggressive skin carcinoma and melanoma at a very early age (<8). Our previous results showed that primary XP fibroblasts isolated from healthy (non-photo-exposed) skin negatively impact the extracellular matrix and fail to activate the innate immune system. Here, we show for the first time that XP-C fibroblasts also play a major role in cancer cell invasion ex vivo and in vivo through the overexpression of Hepatocyte Growth Factor/Scatter Factor (HGF/SF) in the absence of genotoxic attacks. The use of inhibitors of the activation of the HGF/SF pathway counteracted the effects of XP fibroblasts on the growth of cancer cells, suggesting new perspectives in the care of XP patients. [ABSTRACT FROM AUTHOR]

Hereditary tyrosinemia type 1 is an autosomal recessive disorder caused by mutations (pathogenic variants) in fumarylacetoacetate hydrolase, an enzyme involved in tyrosine degradation. Its loss results in the accumulation of toxic metabolites that mainly affect the liver and kidneys and can lead to severe liver disease and liver cancer. Tyrosinemia type 1 has a global prevalence of approximately 1 in 100,000 births but can reach up to 1 in 1,500 births in some regions of Québec, Canada. Mutating functionally related "modifier' genes (i.e. genes that, when mutated, affect the phenotypic impacts of mutations in other genes) is an emerging strategy for treating human genetic diseases. In vivo somatic genome editing in animal models of these diseases is a powerful means to identify modifier genes and fuel treatment development. In this study, we demonstrate that mutating additional enzymes in the tyrosine catabolic pathway through liver-specific genome editing can relieve or worsen the phenotypic severity of a murine model of tyrosinemia type 1. Neonatal gene delivery using recombinant adeno-associated viral vectors expressing Staphylococcus aureus Cas9 under the control of a liver-specific promoter led to efficient gene disruption and metabolic rewiring of the pathway, with systemic effects that were distinct from the phenotypes observed in whole-body knockout models. Our work illustrates the value of using in vivo genome editing in model organisms to study the direct effects of combining pathological mutations with modifier gene mutations in isogenic settings. [ABSTRACT FROM AUTHOR]

Objective: USP14 (Ubiquitin‐specific‐processing protease 14) is a deubiquitinating enzyme with oncogenic effects in oral squamous cell carcinoma (OSCC). This study aims to identify new substrates of USP14 and elucidate their role in modulating cancer stem‐like cells (CSCs) in OSCC. Materials and Methods: Bioinformatics prediction and docking were performed using UbiBrowser 2.0 and HDOCK, respectively. OSCC cell lines and patient‐derived cells were used for experimental validation, employing co‐immunoprecipitation, cycloheximide chase assays, and tumor sphere formation to evaluate the effects of USP14 on SOX2 stability, ubiquitination, and CSC phenotypes. Results: USP14 upregulation was associated with worse overall survival and progression‐free interval in OSCC. USP14 interacted with SOX2 with its ubiquitin carboxyl‐terminal hydrolase domain. USP14 knockdown impaired SOX2 stability by increasing its polyubiquitination. Ectopic overexpression of wild‐type USP14, but not the hydrolase‐deficient‐mutant USP14C114A, enhanced SOX2 stability by reducing polyubiquitination. USP14 knockdown suppressed OSCC cell proliferation, colony formation, and tumor sphere formation in vitro and tumor growth in vivo. However, the reduction of CSC markers following USP14 knockdown was mitigated by overexpressing SOX2. These findings were verified in OSCC patient‐derived CSC cells. Conclusion: This study revealed a USP14‐SOX2 axis regulating the CSC properties of OSCC. [ABSTRACT FROM AUTHOR]

Objective: Anterior disc displacement (ADD) is a common clinical issue and may cause osteoarthritis (OA). However, the research of protein changes in synovial fluid as disease development marker and potential treatment clue is still insufficient. Materials and Methods: We conducted the high‐resolution mass spectrometry (MS) of synovial fluid collected from 60 patients with normal disk position to ADD and ADD with osteoarthritis (OA). The proteins with significant changes among the 3 groups were analyzed by biological information and further validated by in primary rat condyle chondrocytes and OA animal model. Results: FGL2, THBS4, TNC, FN1, OMD etc. were significantly increased in ADD without OA (p < 0.05), which reflected the active extracellular matrix and collagen metabolism. FGFR1, FBLN2, GRB2 etc. were significantly increased in ADD with OA group (p < 0.05), which revealed an association with apoptosis and ferroptosis. Proteins such as P4HB, CBLN4, FHL1, VIM continuously increase in the whole disease progress (p < 0.05). Both the in vitro and in vivo results are consistent with protein changes detected in MS profile. Conclusion: This study firstly provides the expression changes of proteins from normal disc condyle relationship toward ADD with OA, which can be selected and studied further as disease progress marker and potential treatment targets. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the inhibitory effects of STM2457, which is a novel METTL3 (m6A writer) inhibitor, both as a monotherapy and in combination with anlotinib, in the treatment of oral squamous cell carcinoma (OSCC) both in vitro and in vivo. Materials and Methods: The efficacy of STM2457 or STM2457 plus anlotinib was evaluated using two OSCC cell lines by CCK8, transwell, colony formation, would‐healing, sphere formation, cell cycle, apoptosis assays, and nude mice tumor xenograft techniques. The molecular mechanism study was carried out by western blotting, qRT‐PCR, MeRIP‐qPCR, immunofluorescence, and immunohistochemistry. Results: STM2457 combined with anlotinib enhanced inhibition of cellular survival/proliferation and promotion of apoptosis in vitro. Moreover, this combinatorial approach exerted a notable reduction in stemness properties and EMT (epithelial‐mesenchymal transition) features of OSCC cells. Remarkably, in vivo studies validated the efficacy of the combination treatment. Mechanistically, our investigations revealed that the combined action of STM2457 and anlotinib exerted downregulatory effects on EGFR (epidermal growth factor receptor) expression in OSCC cells. Conclusions: The combination of STM2457 and anlotinib targeting EGFR exerted a multiple anti‐tumor effect. In near future, anlotinib combined with STM2457 may provide a novel insight for the treatment of OSCC. [ABSTRACT FROM AUTHOR]

Objectives: Tumor‐associated neutrophils (TANs) are among the most abundant inflammatory cells in tumor microenvironment (TME). Aldehyde dehydrogenase 3A1 (ALDH3A1) is significantly reduced in oral squamous cell carcinoma (OSCC), ALDH3A1 overexpression suppresses tumorigenesis by inhibiting inflammation. This study investigated the relationship and mechanisms underlying the crosstalk between ALDH3A1 and TANs in OSCC. Materials and Methods: Immunohistochemistry and immunofluorescence were performed to investigate the abundance of TANs and the expression of ALDH3A1. dHL‐60 were induced with tumor‐conditioned media and recombinant IL‐6/IL‐8. The expression of key proteins in PI3K/AKT/NF‐κB pathway were detected by RT‐PCR and western blot. A xenograft model was utilized to examine the effect of ALDH3A1 on tumorigenicity and polarization of TANs. Results: In patients with OSCC, TANs significantly increased and were associated with a worse prognosis. Additionally, ALDH3A1 negatively correlated with TANs infiltration and especially the N2 phenotype which was the prominent part in OSCC. Furthermore, our study demonstrated that tumor‐derived IL‐8 drives ALDH3A1‐mediated TANs N2 polarization in the TME through PI3K/AKT/NF‐κB pathway in vitro and in vivo. Conclusion: Our results indicate that TANs can serve as a prognostic biomarker and ALDH3A1 could be a promising therapeutic target for regulating TANs N2 polarization in antitumor therapy. [ABSTRACT FROM AUTHOR]

Acute diarrheal diseases are a leading cause of childhood mortality and morbidity worldwide. Psidium guajava has been globally used for its antidiarrheal potential. We conducted a systematic review of scientific articles published up to the year 2021, which included in vivo pre‐clinical tests and clinical trials involving patients with acute infectious diarrhea to verify the antidiarrheal, antibacterial and antispasmodic effects of galenic preparations or phytopharmaceuticals from P. guajava. PRISMA and Rayyan were used as tools for the selection of studies collected in four databases (Pubmed, Scopus, Web of Science and Science Direct). The keywords used to carry out the search were: 'Psidium guajava', 'guava', 'antidiarrhe*' and 'diarrhe*', joined by Boolean operators 'OR' or 'AND'. The characteristics of studies in animal models of acute diarrhea induction, as well as in vivo and in vitro motility and microbiological tests linked with its main pathophysiological mechanisms, were collected. Twenty‐three articles were included. Twenty (87%) of these reported heterogenic preclinical studies, predominating pharmacological studies of efficacy against conventional antidiarrheal agents, which utilized relevant outcomes and models of infectious diarrhea from the top pathogens in the clinic along with classical castor oil‐induced diarrhea associated with motility tests. Only three articles (13%) corresponded to clinical trials investigating the efficacy, dose and safety of these preparations. Most studies reported positive results and significant mechanistic evidence from antibacterial, anti‐motility, anti‐secretory and protective/anti‐inflammatory perspectives. However, further studies are needed to define the clinical significance and safety treatment with P. guajava extracts. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Objectives: Exposure to benzo[α]pyrene (BaP) increases the incidence and severity of allergic rhinitis (AR), but the underlying mechanisms remain unclear. Thus, we investigated the in vivo effects of BaP exposure on mucus hypersecretion and tissue remodeling in a rat model of AR. Methods: Female Sprague–Dawley rats were randomly divided into 4 groups: a negative control group, a group of healthy rats exposed to BaP, a group of rats with ovalbumin (OVA)-induced AR, and a group of AR model rats exposed to BaP. Nasal symptoms and levels of OVA-specific serum immunoglobulin E (IgE) were measured in each individual rat. Moreover, examination of goblet cell hyperplasia and collagen deposition was carried out with periodic acid-Schiff (PAS) staining and Masson trichrome (MT) staining. Mucin 5AC (MUC5AC) expression was assessed by immunohistochemistry. Results: BaP significantly increased the number of sneezes, the number of nasal rubs and the levels of OVA-specific serum IgE in rats with AR. Statistically significant differences in goblet cell hyperplasia and collagen deposition were observed between the BaP-exposed AR model group and the AR model group. Immunohistochemical results showed that the nasal mucosa of AR model rats displayed markedly elevated MUC5AC expression after BaP exposure. Conclusion: Our data indicate that mucus hypersecretion and the development of nasal remodeling might be pathophysiologic mechanisms underlying increased susceptibility to AR after exposure to BaP. [ABSTRACT FROM AUTHOR]

Introduction: A minimally invasive alternative to surgery for treating pneumothorax has been developed, aiming to reduce risks while maintaining efficacy. This study conducted basic experiments using ex vivo and in vivo pig lung employing a super-thin catheter for treatment. This new device injects fibrin glue directly into the responsible lesion to close the air leak, which has two features: thin design and double-lumen. Methods: The experimental setup involved utilizing trachea and both lung specimens from pigs under positive pressure ventilation. To simulate pneumothorax, artificial fistulas were created on the lung surfaces. The super-thin catheter, guided through a bronchoscope near the fistula, was used to embolize the peripheral bronchus by injecting a fibrin preparation. Then, an air leak test was conducted afterward to assess the efficacy of the treatment. Additionally, a similar pneumothorax model was induced in alive pig under general anesthesia to evaluate its curability. Results: In the extracted pig lungs, embolization was performed in 21 cases, resulting in the cessation of air leaks in 19 cases, corresponding to a 90.5% cure rate. Notably, no major adverse events occurred with the treatment devices. Similarly, in living pigs, pneumothorax was successfully treated, with no recurrence observed up to the seventh postoperative day. Conclusion: The novel treatment device utilizing a super-thin catheter offers a minimally invasive and highly curative option for pneumothorax. These promising results suggest the potential for further development and human clinical trials, which could revolutionize the treatment of pneumothorax, reducing risks and improving outcomes. [ABSTRACT FROM AUTHOR]

The research aimed to evaluate the antioxidative and antibacterial characteristics of aqueous sumac extract on methicillin-resistant Staphylococcus aureus through in-vitro and in-vivo study. Sumac extract has been obtained through the soaking method, and its antioxidant properties were gauged using the DPPH free radical scavenging method. The minimum inhibitory concentration (MIC) of sumac extract was determined on S. aureus obtained from hospitalized patients, as well as an assessment of biofilm-formation and the release of bacterial intracellular compounds. in vivo experimentation involved injecting bacteria (108 cfu/ml) into mice, which subsequently manifested indicators of symptoms of infection, and the number of bacteria within their bloodstream was quantified. The Sumac extract demonstrated strong antioxidant properties at concentrations of 1000 mg/ml. Furthermore, the agar tests for the gram staining, mannitol, coagulase, and DNase revealed that 190 cultured bacteria samples were identified as Staphylococcus aureus. These bacteria were resistant to clindamycin, ciprofloxacin, and methicillin antibiotics, but sensitive to erythromycin and penicillin antibiotics. Additionally, the bacteria displayed significant methicillin resistance and formed a strong biofilm (65.78%). The sumac extract showed a MIC range of 125–1000 µg/ml against Staphylococcus aureus. Treatment with concentrations above the MIC was found to prevent the formation of biofilm and increase the release of bacterial intracellular compounds. Sumac extract led to a decrease in bacterial count in the blood of mice and reduced signs of infection. Sumac extract demonstrated powerful antioxidant and antibacterial effects against resistant microorganisms, suggesting its potential as a promising compound for the treatment of resistant infections in future research. [ABSTRACT FROM AUTHOR]

Fermented red ginseng (FRG) enhances the bioactivity and bioavailability of ginsenosides, which possess various immunomodulatory, antiaging, anti-obesity, and antidiabetic properties. However, the effects of FRG extract on muscle atrophy and the underlying molecular mechanisms remain unclear. This study aimed to elucidate the effects of FRG extract on muscle atrophy using both in vitro and in vivo models. In vitro experiments used dexamethasone (DEX)-induced C2C12 myotubes to assess cell viability, myotube diameter, and fusion index. In vivo experiments were conducted on hind limb immobilization (HI)-induced mice to evaluate grip strength, muscle mass, and fiber cross-sectional area (CSA) of the gastrocnemius (GAS), quadriceps (QUA), and soleus (SOL) muscles. Molecular mechanisms were investigated through the analysis of key signaling pathways associated with muscle protein synthesis, energy metabolism, and protein degradation. FRG extract treatment enhanced viability of DEX-induced C2C12 myotubes and restored myotube diameter and fusion index. In HI-induced mice, FRG extract improved grip strength, increased muscle mass and CSA of GAS, QUA, and SOL muscles. Mechanistic studies revealed that FRG extract activated the insulin-like growth factor 1/protein kinase B (Akt)/mammalian target of rapamycin signaling pathway, promoted muscle energy metabolism via the sirtuin 1/peroxisome proliferator-activated receptor gamma-coactivator-1α pathway, and inhibited muscle protein degradation by suppressing the forkhead box O3a, muscle ring-finger 1, and F-box protein (Fbx32) signaling pathways. FRG extract shows promise for ameliorating muscle atrophy by modulating key molecular pathways associated with muscle protein synthesis, energy metabolism, and protein degradation, offering insights for future drug development. [ABSTRACT FROM AUTHOR]

Garcinia kola is a medicinal food commonly consumed in Sub-Sahara Africa, for which Kolaviron (KV) is the active portion. As a follow-up to our earlier chemopreventive studies, we investigated the chemotherapeutic effects of KV on experimentally induced mammary carcinogenesis in female Wistar rats. Mammary carcinogenesis was induced using 80 mg/kg of 7,12-dimethylbenzanthracene (DMBA) administered by oral gavage. One hundred-fifty days post-DMBA induction, estrogen receptor-α (ER-α) levels were determined in the experimental rats before treatment with KV commenced. Treatment was done using 50, 100, and 200 mg/kg KV thrice a week for 4 weeks, after which the experiment was terminated. Significantly higher levels of estrogen receptor-α, CYP 1A1, malondialdehyde, formation of lobular neoplastic cells, epithelial hyperplasia, lymphocyte infiltration, and increased cytokine (interleukin-6 and tumor necrosis factor-α) activity were observed in DMBA-induced rats, which were attenuated in KV-treated rats. Tyrosine metabolism was exclusively enriched in DMBA-induced rats in contrast to KV-treated rats. Collectively, the results point to the chemotherapeutic potential of KV. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction is implicated in heat-induced skeletal muscle (SKM) injury and its underlying mechanisms remain unclear. Evidence suggests that cellular ions and molecules, including divalent cations and adenine nucleotides, are involved in the regulation of mitochondrial function. In this study, we examined Ca2+, Mg2+, and NAD+ levels in mouse C2C12 myoblasts and SKM in response to heat exposure. During heat exposure, mitochondrial Ca2+ levels increased significantly, whereas cytosolic Ca2+ levels remained unaltered. The mitochondrial Ca2+ levels in the SKM of heat-exposed mice were 28% higher compared to control mice. No changes in cytosolic Ca2+ were detected between the two groups. Following heat exposure, cytosolic and mitochondrial Mg2+ levels were reduced by 47% and 23% in C2C12 myoblasts, and by 51% and 44% in mouse SKMs, respectively. In addition, heat exposure decreased mitochondrial NAD+ levels by 32% and 26% in C2C12 myoblasts and mouse SKMs, respectively. Treatment with the NAD+ precursor nicotinamide riboside (NR) partially prevented heat-induced depletion of NAD+. Additionally, NR significantly reduced heat-increased mitochondrial fission, mitochondrial depolarization, and apoptosis in C2C12 myoblasts and mouse SKMs. No effects of NR on heat-induced changes in intracellular Ca2+ and Mg2+ levels were observed. This study provides in vitro and in vivo evidence that acute heat stress causes alterations in mitochondrial Ca2+, Mg2+, and NAD+ homeostasis. Our results suggest mitochondrial NAD+ homeostasis as a therapeutic target for the prevention of heat-induced SKM injury. [ABSTRACT FROM AUTHOR]

Summary: The rat's model evaluated the function of sprouted beans enriched with probiotic Lactiplantibacillus plantarum 299v in alleviating dyslipidaemia, inflammation and disturbed redox homeostasis caused by a high‐lard diet. Sprouted beans improved the total antioxidant capacity of serum and liver, regardless of whether the feeds had a higher content of low‐molecular antioxidants or were additionally enriched with probiotics. The reduction of inflammation (lowered level of C‐reactive protein) and restoration of triglycerides and total cholesterol to the levels recorded in the control group (AIN‐93M) were especially observed in the group supplemented with the control adzuki bean. Introducing sprouted legumes (both the control and probiotic‐rich) improved microbiota activity affected by a high‐lard diet. The highest, desirable reduction of urease (by 80%) and tryptophanase (by 78%) activity was found in the groups fed with probiotic‐rich adzuki and mung bean sprouts respectively. Sprouted beans improve the metabolism of individuals subjected to a diet with an increased fat‐to‐carbohydrate energy ratio, especially concerning oxidative stress injury and microbiota activity. [ABSTRACT FROM AUTHOR]