Current Progress of Platelet-Rich Derivatives in Cartilage and Joint Repairs.

In recent years, several types of platelet concentrates have been investigated and applied in many fields, particularly in the musculoskeletal system. Platelet-rich fibrin (PRF) is an autologous biomaterial, a second-generation platelet concentrate containing platelets and growth factors in the form of fibrin membranes prepared from the blood of patients without additives. During tissue regeneration, platelet concentrates contain a higher percentage of leukocytes and a flexible fibrin net as a scaffold to improve cell migration in angiogenic, osteogenic, and antibacterial capacities during tissue regeneration. PRF enables the release of molecules over a longer period, which promotes tissue healing and regeneration. The potential of PRF to simulate the physiology and immunology of wound healing is also due to the high concentrations of released growth factors and anti-inflammatory cytokines that stimulate vessel formation, cell proliferation, and differentiation. These products have been used safely in clinical applications because of their autologous origin and minimally invasive nature. We focused on a narrative review of PRF therapy and its effects on musculoskeletal, oral, and maxillofacial surgeries and dermatology. We explored the components leading to the biological activity and the published preclinical and clinical research that supports its application in musculoskeletal therapy. The research generally supports the use of PRF as an adjuvant for various chronic muscle, cartilage, and tendon injuries. Further clinical trials are needed to prove the benefits of utilizing the potential of PRF.

Breast Milk Excretion of Dinalbuphine Sebacate Injection Administered After Cesarean Section.

Ensuring the safety of analgesics during lactation is crucial for women of childbearing potential. Available data regarding the transfer of nalbuphine for postoperative acute pain via breast milk are limited to the postmarketing experience. This lactation study aimed to assess nalbuphine and dinalbuphine sebacate concentrations in breast milk from lactating women with postoperative pain treated with dinalbuphine sebacate extended-release injection (150 mg dinalbuphine sebacate/2 mL Naldebain). Breast milk was collected throughout the 5-day posthospitalization interval from 20 mothers injected with one dose of extended-release dinalbuphine sebacate intramuscularly. Maternal safety was assessed during the study period. Nalbuphine was detectable in 71% of milk samples collected from all mothers, whereas dinalbuphine sebacate was undetectable or below the quantitation limit (0.1 ng/mL). The mean nalbuphine concentration in milk was approximately 10.55 ng/mL, with the peak concentration reaching up to 12.7 ng/mL. The mean relative infant dose was 0.39% (coefficient of variation, 65%). The mean pain intensity at rest was reduced to mild pain from Day 2 morning to discharge. Overall, the maternal safety profile was tolerable. The breast milk of women who receive one dose of dinalbuphine sebacate injection postpartum contains low nalbuphine concentration. In addition, dinalbuphine sebacate injection potentially reduces maternal pain intensity during the first postpartum week and offers low toxicity risk among breastfed infants.

Anticancer Activities of 9-chloro-6-(piperazin-1-yl)-11H-indeno[1,2-c] quinolin-11-one (SJ10) in Glioblastoma Multiforme (GBM) Chemoradioresistant Cell Cycle-Related Oncogenic Signatures.

Current anticancer treatments are inefficient against glioblastoma multiforme (GBM), which remains one of the most aggressive and lethal cancers. Evidence has shown the presence of glioblastoma stem cells (GSCs), which are chemoradioresistant and associated with high invasive capabilities in normal brain tissues. Moreover, accumulating studies have indicated that radiotherapy contributes to abnormalities in cell cycle checkpoints, including the G1/S and S phases, which may potentially lead to resistance to radiation. Through computational simulations using bioinformatics, we identified several GBM oncogenes that are involved in regulating the cell cycle. Cyclin B1 (CCNB1) is one of the cell cycle-related genes that was found to be upregulated in GBM. Overexpression of CCNB1 was demonstrated to be associated with higher grades, proliferation, and metastasis of GBM. Additionally, increased expression levels of CCNB1 were reported to regulate activation of mitogen-activated protein kinase 7 (MAPK7) in the G2/M phase, which consequently modulates mitosis; additionally, in clinical settings, MAPK7 was demonstrated to promote resistance to temozolomide (TMZ) and poor patient survival. Therefore, MAPK7 is a potential novel drug target due to its dysregulation and association with TMZ resistance in GBM. Herein, we identified MAPK7/extracellular regulated kinase 5 (ERK5) genes as being overexpressed in GBM tumors compared to normal tissues. Moreover, our analysis revealed increased levels of the cell division control protein homolog (CDC42), a protein which is also involved in regulating the cell cycle through the G1 phase in GBM tissues. This therefore suggests crosstalk among CCNB1/CDC42/MAPK7/cluster of differentiation 44 (CD44) oncogenic signatures in GBM through the cell cycle. We further evaluated a newly synthesized small molecule, SJ10, as a potential target agent of the CCNB1/CDC42/MAPK7/CD44 genes through target prediction tools and found that SJ10 was indeed a target compound for the above-mentioned genes; in addition, it displayed inhibitory activities against these oncogenes as observed from molecular docking analysis.

Transcriptomic-Based Identification of the Immuno-Oncogenic Signature of Cholangiocarcinoma for HLC-018 Multi-Target Therapy Exploration.

Cholangiocarcinomas (CHOLs), hepatobiliary malignancies, are characterized by high genetic heterogeneity, a rich tumor microenvironment, therapeutic resistance, difficulty diagnosing, and poor prognoses. Current knowledge of genetic alterations and known molecular markers for CHOL is insufficient, necessitating the need for further evaluation of the genome and RNA expression data in order to identify potential therapeutic targets, clarify the roles of these targets in the tumor microenvironment, and explore novel therapeutic drugs against the identified targets. Consequently, in our attempt to explore novel genetic markers associated with the carcinogenesis of CHOL, five genes (SNX15, ATP2A1, PDCD10, BET1, and HMGA2), collectively termed CHOL-hub genes, were identified via integration of differentially expressed genes (DEGs) from relatively large numbers of samples from CHOL GEO datasets. We further explored the biological functions of the CHOL-hub genes and found significant enrichment in several biological process and pathways associated with stem cell angiogenesis, cell proliferation, and cancer development, while the interaction network revealed high genetic interactions with a number of onco-functional genes. In addition, we established associations between the CHOL-hub genes and tumor progression, metastasis, tumor immune and immunosuppressive cell infiltration, dysfunctional T-cell phenotypes, poor prognoses, and therapeutic resistance in CHOL. Thus, we proposed that targeting CHOL-hub genes could be an ideal therapeutic approach for treating CHOLs, and we explored the potential of HLC-018, a novel benzamide-linked small molecule, using molecular docking of ligand-receptor interactions. To our delight, HLC-018 was well accommodated with high binding affinities to binding pockets of CHOL-hub genes; more importantly, we found specific interactions of HLC-018 with the conserved sequence of the AT-hook DNA-binding motif of HMGA2. Altogether, our study provides insights into the immune-oncogenic phenotypes of CHOL and provides valuable information for our ongoing experimental validation.

CD133 Targeted PVP/PMMA Microparticle Incorporating Levamisole for the Treatment of Ovarian Cancer.

Levamisole (LEVA) is used to treat worm infections, but it can also inhibit cancer cell growth by inhibiting the aldehyde dehydrogenase pathway. Therefore, here, we developed a drug carrier targeting CD133, a biomarker overexpressed in ovarian cancer cells. The particle structure and cytotoxicity of the prepared LEVA-containing particles-called LEVA/PVP/PMMA microparticles (MPs) (because it used matrix material polyvinylpyrrolidone (PVP) and poly(methylmethacrylate) (PMMA))-were investigated in the ovarian cancer cell lines SKOV-3 and CP70. The particle size of the MPs was determined to be 1.0-1.5 µm and to be monodispersed. The hydrophilic property of PVP created a porous MP surface after the MPs were soaked in water for 20 min, which aided the leaching of the hydrophilic LEVA out of the MPs. The encapsulation efficiency of LEVA/PVP/PMMA MPs could reach up to 20%. Free-form LEVA released 50% of drugs in <1 h and 90% of drugs in 1 day, whereas the drug release rate of LEVA/PVP/PMMA MPs was much slower; 50% released in 4 h and only 70% of drugs released in 1 day. In the in vitro cell model test, 5 mM free-form LEVA and 0.1 g/mL CD133 targeted LEVA/PVP/PMMA MPs reduced SKOV-3 cell viability by 60%; 0.1 g/mL LEVA/PVP/PMMA MPs was equivalent to a similar dosage of the free drug. In addition, the cytotoxicity of CD133-conjugated LEVA/PVP/PMMA MPs shows a different cytotoxicity response toward cell lines. For SKOV-3 cells, treatment with free-form LEVA or CD133-conjugated LEVA/PVP/PMMA MPs exerted dose-dependent cytotoxic effects on SKOV-3 cell viability. However, CD133-conjugated LEVA/PVP/PMMA MPs demonstrated no significant dose-dependent cytotoxic efficacy toward CP70 cells.

Evaluation of Chitosan Derivative Microparticles Encapsulating Superparamagnetic Iron Oxide and Doxorubicin as a pH-Sensitive Delivery Carrier in Hepatic Carcinoma Treatment: An in vitro Comparison Study.

We developed a novel, pH-sensitive drug delivery microparticle based on N-palmitoyl chitosan (NPCS) to transport the superparamagnetic iron oxide (SPIO) and anticancer drug doxorubicin (DOX). The characteristics of NPCS were characterized through nuclear magnetic resonance. Our results based on testing of volume swelling in multiple pH aqueous solutions revealed that the modified chitosan had a pH-sensitive property. The morphology and size of the DOX-SPIO/NPCS microparticles were investigated using transmission electron microscopy and scanning electron microscopy. The statistical result of microparticles had diameter of 185 ± 87 nm. Surface chemical moieties of DOX-SPIO/NPCS microparticles were confirmed using attenuated total reflection Fourier transform infrared spectroscopy and indicated the existence of mostly hydrophilic groups such as -OH, -C=O, and -C-O-C-. Transmission electron microscopy revealed the dark contrast of SPIO dots encapsulated in the NPCS matrix. Nuclear magnetic resonance T2-weighted magnetic resonance imaging confirmed that the produced DOX-SPIO/NPCS microparticles still exhibited T2 relaxation durations as short as 37.68 ± 8.69 ms (under administration of 2.5 µg/mL), which is comparable to the clinically required dosage. In the drug release profile, the DOX-SPIO/NPCS drug delivery microparticle was accelerated in an acidic environment (pH 6.5) compared with that in a basic environment. Microparticles in a cytotoxicity assay (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay) revealed that DOX-SPIO/NPCS microparticles had better antitumor ability than did free-form of DOX. Additionally, microparticles loaded with 0.5-5 µg/mL DOX in an acidic environment (pH 6.5) demonstrated higher efficacy against Hep G2 cell growth, possibly because of the swelling effect of NPCS, resulting in volume expansion and easy drug release. Accordingly, these large DOX-SPIO/NPCS microparticles showed potential for application as a pH-sensitive drug delivery system and as chemoembolization particles for hepatic carcinoma therapy.

Relationships of Age and Sex with Cytokine Content and Distribution in Human Platelet Fibrin Gels.

We aimed to determine relationships between age and sex with cytokine content and distribution in human platelet-rich fibrin (PRF) gel. Rabbit PRF was harvested from whole blood (n = 6). Human PRF was collected from 36 healthy volunteers (1:1 men:women) without systemic diseases and not current undergoing medical treatment. Histological analysis and optical microscopy were used to assess the three-dimensional structure of the PRF network. Enzyme-linked immunosorbent assays, quantification of adenosine triphosphate, and bioluminescence imaging of PRF sections were used to assess cytokine and entrapped platelet distribution. Three-dimensional structures of fibrin networks revealed concentration gradients of the platelet-derived growth factor beta beta homodimer and the transforming growth factor-beta 1. Histological analysis of PRF sections (from the red blood cell end to the plasma end of a clot) showed a gradual increase in average porosity, most prominently in PRF clots from young and middle-aged men and women, and a decrease in compactness along the longitudinal axis of the PRF gel. The end of the PRF gel closest to the red blood cell layer is the essence of the PRF clot, and the ability to generate platelets depends on sex and age in humans.

Development and application of micro-polysaccharide drug carriers incorporating doxorubicin and superparamagnetic iron oxide for bimodality treatment of hepatocellular carcinoma.

In this study, we demonstrated a novel polyelectrolyte microparticle, doxorubicin(DOX)-superparamagnetic iron oxide (SPIO)-chondroitin sulfate (CS)/chitosan (CHI)microparticles (MPs), as a drug delivery system for hepatic cancer treatment. We also investigated the properties of these microparticles through composition determination, formulation tests, in vitro study, and in vivo study. The results showed that our DOX-SPIO-CS/CHI MPs had an average diameter of 1.43±0.54µm and exhibited a spherical shape. The encapsulation efficiency of this drug carrier was approximately 31±8.07%, according to our spectroscopic determination. The results of release profile test revealed the sustained-release behavior of DOX-SPIO-CS/CHI MPs, which released 51.5% of DOX within 48h of the testing period. According to the results of a cell viability assay and an animal study, the DOX-SPIO-CS/CHI MPs exhibited stronger cytotoxicity than did free DOX when it was administered to Hep G2 and Huh-6 human liver cancer cell lines in vitro and to nude mice of Hep G2/Huh-6-bearing mice model in vivo.