Linnetthybo8517

Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths globally. Treatment-related adverse effects and development of drug resistance limit the available treatment options for most patients. Therefore, newer drug candidates and drug delivery systems that have limited adverse effects with significant anti-cancer efficacy are needed. For NSCLC treatment, delivering drugs via inhalation is highly beneficial as it requires lower doses and limits systemic toxicity. Bedaquiline (BQ), an FDA-approved anti-tuberculosis drug has previously shown excellent anti-cancer efficacy. However, poor aqueous solubility limits its delivery via the lungs. In this project, we developed inhalable BQ-loaded cubosome (BQLC) nanocarriers against NSCLC. The BQLC were prepared using a solvent evaporation technique with the cubosomal nanocarriers exhibiting a particle size of 150.2 ± 5.1 nm, zeta potential of (+) 35.4 ± 2.3 mV, and encapsulation efficiency of 51.85 ± 4.83%. The solid-state characterization (DSC and XRD) confirmed drug encapsulation and in an amorphous form within the cubosomes. selleck The BQLC nanocarriers showed excellent aerodynamic properties after nebulization (MMAD of 4.21 ± 0.53 µm and FPF > 75%). The BQLC displayed enhanced cellular internalization and cytotoxicity with a ~ 3-fold reduction in IC50 compared to free BQ in NSCLC (A549) cells, after 48 h treatment. The BQLC suppressed cell proliferation via apoptotic pathway, further inhibited colony formation, and cancer metastasis in vitro. Additionally, 3D-tumor simulation studies established the anti-cancer efficacy of cubosomal nanocarriers as compared to free BQ. This is the first study exploring the potential of cubosomes as inhalation therapy of repurposed drug, BQ and the results suggest that BQLC may be a promising NSCLC therapy due to excellent aerosolization performance and enhanced anti-cancer activity.Hot melt extrusion (HME) is a technique applied in the preparation of pharmaceutical amorphous solid dispersions (ASD). Notably it is important to prevent thermal degradation of heat-sensitive drugs during HME. In this study, we present a new strategy to improve chemical stability of pharmaceutical compounds during HME through the formation of eutectics with small molecules. Resveratrol (RES) was selected as the model compound because it is a heat-liable natural product with a very high melting point of 267 °C. When heated at its melting point for 3 min, it degrades by 40%. RES can co-crystallize with nicotinamide (NIC) in solution, however, it can only form a eutectic with NIC during heating. HPMCAS was selected as the polymer matrix and the drug loading of RES was fixed as 20% (weight ratio). The lowest extrusion temperature that can result to RES-HPMCAS ASD is 215 °C. At this temperature, RES shows 7.36% degradation during extrusion. Replacement of 21.4% HPMCAS with NIC decreased the melting temperature of NIC and thus lowered the minimal extrusion temperature to 155 °C. This effectively prevented thermal degradation of RES without negatively affecting non-sink dissolution. The only extra cost for this method is stricter storage conditions (low temperature and low humidity) due to the low glass transition temperature of NIC. Similar strategy may be applied to other heat-liable drugs in similar ways. This study demonstrates the use of eutectic formation for preventing thermal degradation of drug during extrusion of ASD.Glucagon-like peptide-1 (GLP-1) has been considered to be a promising peptide for treatment of type 2 diabetes mellitus (T2DM). However, the extremely short half-life (minutes) of native GLP-1 limits its clinical application potential. Here, we designed two GLP-1 analogues by genetic fusion of GLP-1 to one or two tandem human serum albumin-binding designed ankyrin repeat proteins (DARPins), denoted as GLP-DARPin or GLP-2DARPin. The two DARPin-fusion GLP-1 proteins were expressed in E. coli and purified, followed by measurements of their bioactivities and half-lives in mice. The results revealed that the half-life of GLP-2DARPin, binding two HSA molecules, was approximately 3-fold longer than GLP-DARPin (52.3 h versus 18.0 h). In contrast, the bioactivity results demonstrated that the blood glucose-lowering effect of GLP-DARPin was more potent than that of GLP-2DARPin. The oral glucose tolerance tests indicated that blood glucose levels were significantly reduced for at least 48 h by GLP-DARPin, but were reduced for only 24 h by GLP-2DARPin. Injected once every two days, GLP-DARPin substantially reduced blood glucose levels in streptozotocin (STZ)-induced diabetic mice to the same levels as normal mice. During the treatment course, GLP-DARPin significantly reduced the food intake and body weight of diabetic mice up to approximately 17% compared with the control group. A histological analysis revealed that GLP-DARPin alleviated islet loss in diabetic mice. These findings suggest that long-acting GLP-DARPin holds great potential for further development into drugs for the treatment of T2DM and obesity. Meanwhile, our data indicate that albumin-binding DARPins can be used as a universal scaffold to improve the pharmacokinetic profiles and pharmacological activities of therapeutic peptides and proteins.Electrospinning is an innovative technique that allows production of nanofibers and microfibers by applying a high voltage to polymer solutions of melts. The properties of these fibers - which include high surface area, high drug loading capacity, and ability to be manufactured from mucoadhesive polymers - may be particularly useful in a myriad of drug delivery and tissue engineering applications. The last decade has witnessed a surge of interest in the application of electrospinning technology for the fabrication of vaginal drug delivery systems for the treatment and prevention of diseases associated with women's sexual and reproductive health, including sexually transmitted infections (e.g. infection with human immunodeficiency virus and herpes simplex virus) vaginitis, preterm birth, contraception, multipurpose prevention technology strategies, cervicovaginal cancer, and general maintenance of vaginal health. Due to their excellent mechanical properties, electrospun scaffolds are also being investigated as next-generation materials in the surgical treatment of pelvic organ prolapse. In this article, we review the latest advances in the field.Huaier, a traditional Chinese medicine, is currently used to treat certain types of cancer in the clinic and is also regarded as an immune-modulating and immune-enhancing agent that regulates immune cells. Emerging evidence indicates that an imbalance of immune cells, such as CD4+ T helper (Th) lymphocytes, contributes to the progression of immune thrombocytopenia (ITP), but the effects of Huaier on the regulation of CD4+ T cells are not yet fully elucidated. In the present study, Jurkat cells and peripheral blood mononuclear cells (PBMCs) from patients with ITP and healthy volunteers were treated with Huaier aqueous extract (HR). The CCK-8 assay revealed that HR suppressed the proliferation of Jurkat cells in a dose-dependent manner, whereas 3 mg/mL could decrease cell viability by 50%. link2 At the latter concentration, the activation of CD4+ T cells from patients with ITP was partially attenuated. In addition, HR could correct the unbalanced Th1/Th2 polarization and inhibit the secretion of pro-inflammatory factors interleukin (IL)-2, tumor necrosis factor-α, and interferon-γ. It also suppressed Treg and facilitated Th17 differentiation, but did not change the levels of IL-10 and transforming growth factor-β. Thus, this study provides more information on how Huaier regulates cellular immunity and improves our understanding of the use of Huaier in ITP.

To describe the pattern of the nerves in the inferocentral whorl region of the human corneal subbasal nerve plexus (SBNP) in health and diseases known to affect the subbasal nerves.

Laser-scanning in vivo confocal microscopy (IVCM) was used to image the SBNP bilaterally in 91 healthy subjects, 39 subjects with type 2 diabetes mellitus (T2DM), and 43 subjects with Parkinson's disease (PD). Whorl regions were classified according to nerve orientation relative to age and health/disease status.

Of 346 examined eyes, 300 (86.7%) had an identifiable whorl pattern. In healthy subjects, a clockwise nerve orientation of the whorl was most common (67.9%), followed by non-rotatory or 'seam' morphology (21.4%), and counterclockwise (10.7%). The clockwise orientation was more prevalent in healthy subjects than in T2DM or PD (P<0.001). Healthy individuals below 50 years of age had a predominantly clockwise orientation (93.8%) which was reduced to 51.9% in those over 50 years (P<0.001). Age but not disease statu regulating these changes warrant further investigation.Glioblastoma (GBM) is considered one of the most common malignant brain tumors, occurring as over 15% of all primary central nervous system and brain neoplasms. The unique and standard treatment option towards GBM involves the combination of surgical resection followed by radiotherapy (RT) and chemotherapy (CT). However, due to the aggressive nature and heterogeneity of GBMs, they remained difficult to treat. Recent findings from preclinical studies have revealed that disruption of the redox balance via using either oxidative or anti-oxidative agents in GBM presented an effective and promising therapeutic approach. A limited number of clinical trials substantially encouraged their concomitant use with RT or CT. Thus, treatment of GBMs may benefit from natural or synthetic antioxidative compounds as novel therapeutics. Despite the presence of variegated in vitro and in vivo studies focusing on safety and efficacy issues of these promising therapeutics, nowadays their translation to clinics is far from applicability due to several challenges. In this review, we briefly introduce the enzymatic and non-enzymatic antioxidant defense systems as well as potential signaling pathways related to the pathogenesis of GBM with a special interest in antioxidant mechanisms. In addition, we describe the advantages and limitations of antioxidant supplementation in GBM cases or disease models as well as growing challenges for GBM therapies with antioxidants in the future.

To perform a meta-analysis to explore factors associated with clinical and structural short-term outcomes in randomized and nonrandomized prospective studies of rotator cuff repair.

Medline, clinicaltrials.gov, and Mendeley were searched for literature published from January 2000 to December 2020 to identify randomized controlled trials (RCT) and nonrandomized prospective cohort studies (PCS) describing the outcome of surgical repair of full-thickness rotator cuff tears. Study quality was assessed by two independent reviewers. We calculated standardized mean difference (SMD) from baseline to follow-up in each trial arm, preferably at 12 months follow-up. Between-study heterogeneity of outcomes, small-study effects and rates of retear were assessed. link3 Meta-regression was performed to estimate associations between prespecified variables and clinical and structural outcomes.

Outcomes in 64 RCT and 19 PCS trial arms were analyzed. Median age was 59 years. There was substantial between-study heterogeneity in clinical outcomes (SMD range .