Glucagon-like peptide-1 analogs: Miracle drugs are blooming?

Glucagon-like peptide-1 (GLP-1), secreted by L cells in the small intestine, assumes a central role in managing type 2 diabetes mellitus (T2DM) and obesity. Its influence on insulin secretion and gastric emptying positions it as a therapeutic linchpin. However, the limited applicability of native GLP-1 stems from its short half-life, primarily due to glomerular filtration and the inactivating effect of dipeptidyl peptidase-IV (DPP-IV). To address this, various structural modification strategies have been developed to extend GLP-1's half-life. Despite the commendable efficacy displayed by current GLP-1 receptor agonists, inherent limitations persist. A paradigm shift emerges with the advent of unimolecular multi-agonists, such as the recently introduced tirzepatide, wherein GLP-1 is ingeniously combined with other gastrointestinal hormones. This novel approach has captured the spotlight within the diabetes and obesity research community. This review summarizes the physiological functions of GLP-1, systematically explores diverse structural modifications, delves into the realm of unimolecular multi-agonists, and provides a nuanced portrayal of the developmental prospects that lie ahead for GLP-1 analogs.

Formation process of extension knee joint contracture following external immobilization in rats.

BACKGROUND: Current research lacks a model of knee extension contracture in rats. AIM: To elucidate the formation process of knee extension contracture. METHODS: We developed a rat model using an aluminum external fixator. Sixty male Sprague-Dawley rats with mature bones were divided into the control group (n = 6) and groups that had the left knee immobilized with an aluminum external fixator for 1, 2, and 3 d, and 1, 2, 3, 4, 6, and 8 wk (n = 6 in each group). The passive extension range of motion, histology, and expression of fibrosis-related proteins were compared between the control group and the immobilization groups. RESULTS: Myogenic contracture progressed very quickly during the initial 2 wk of immobilization. After 2 wk, the contracture gradually changed from myogenic to arthrogenic. The arthrogenic contracture progressed slowly during the 1st week, rapidly progressed until the 3rd week, and then showed a steady progression until the 4rd week. Histological analyses confirmed that the anterior joint capsule of the extended fixed knee became increasingly thicker over time. Correspondingly, the level of transforming growth factor beta 1 (TGF-ß1) and phosphorylated mothers against decapentaplegic homolog 2 (p-Smad2) in the anterior joint capsule also increased with the immobilization time. Over time, the cross-sectional area of muscle fibers gradually decreased, while the amount of intermuscular collagen and TGF-ß1, p-Smad2, and p-Smad3 was increased. Unexpectedly, the amount of intermuscular collagen and TGF-ß1, p-Smad2, and p-Smad3 was decreased during the late stage of immobilization (6-8 wk). The myogenic contracture was stabilized after 2 wk of immobilization, whereas the arthrogenic contracture was stabilized after 3 wk of immobilization and completely stable in 4 wk. CONCLUSION: This rat model may be a useful tool to study the etiology of joint contracture and establish therapeutic approaches.

High-performance and compact integrated photonic dichroic filters and triplexer realized by an efficient inverse design.

Integrated optical filters are key components in various photonic integrated circuits for applications of communication, spectroscopy, etc. The dichroic filters can be flexibly cascaded to construct filters with various channel numbers and bandwidths. Therefore, the development of high-performance and compact dichroic filters is crucial. In this work, we develop the dichroic filters with 1.49/1.55-µm channels by an inverse design. Benefiting from a search-space-dimension control strategy and advanced optimization algorithm, our efficient design method results in two high-performance dichroic filters without and with subwavelength gratings (SWGs). The comparison suggests that SWGs in filters can be useful for loss reduction and footprint compression by dispersion engineering. The developed dichroic filter with SWGs exhibits measured bandwidths of 26/29 nm, excess losses of < 0.5 dB, and crosstalks of <-10 dB with a compact footprint of 2.5 × 22.0 µm2. It has advantages in performance or compactness compared to the previously reported counterparts. A triplexer with a footprint of 10.5 × 117 µm2 is developed based on the dichroic filters, also showing decent overall performance and compactness.

Visible-light photocatalytic degradation of water-soluble polyvinyl alcohol in aqueous solution by Cu2O@TiO2: Optimization of conditions, mechanisms and toxicity analysis.

Polyvinyl alcohol (PVA), a water-soluble synthetic polymer, is one of the most prevalent non-native polyvinyl alcohols found in the environment. Due to its inherent invisibility, its potential for causing severe environmental pollution is often underestimated. To achieve efficient degradation of PVA in wastewater, a Cu2O@TiO2 composite was synthesized through the modification of titanium dioxide with cuprous oxide, and its photocatalytic degradation of PVA was investigated. The Cu2O@TiO2 composite, supported by titanium dioxide, facilitated photocarrier separation and demonstrated high photocatalytic efficiency. Under alkaline conditions, the composite exhibited a 98% degradation efficiency for PVA solutions and a 58.7% PVA mineralization efficiency. Radical capture experiments and electron paramagnetic resonance (EPR) analyses revealed that superoxide radicals primarily drive the degradation process within the reaction system. Throughout the degradation process, PVA macromolecules are broken down into smaller molecules, including ethanol, and compounds containing aldehyde, ketone, and carboxylic acid functional groups. Although the intermediate products exhibit reduced toxicity compared to PVA, they still pose certain toxic hazards. Consequently, further research is necessary to minimize the environmental impact of these degradation products.

Cold air plasma improving rheumatoid arthritis via mitochondrial apoptosis pathway.

Rheumatoid arthritis (RA) has plagued physicians and patients for years due to the lack of targeted treatment. In this study, inspired by the commonality between rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and cancer cells, the therapeutic effects of cold air plasma (CAP) on RA are studied systematically and thoroughly. In/ex vivo results show that CAP with the proper dosage significantly relieves symptoms including synovial hyperplasia, inflammatory infiltration, and angiogenesis and eliminates the root cause by triggering the self-antioxidant capability of the surrounding tissue. The mechanism on the molecular and cellular level is also revealed that the spontaneous reactive oxygen species (ROS) cascade induces the mitochondrial apoptosis pathway on RA-FLS. This study reveals a new strategy for targeted treatment of RA and the mechanistic study provides the theoretical foundation for future development of plasma medicine.

Quorum sensing regulates heteroresistance in Pseudomonas aeruginosa.

The prevalence and genetic mechanism of antibiotic heteroresistance (HR) have attracted significant research attention recently. However, non-genetic mechanism of HR has not been adequately explored. The present study aimed to evaluate the role of quorum sensing (QS), an important mechanism of behavioral coordination in different subpopulations and consequent heteroresistance. First, the prevalence of HR to 7 antibiotics was investigated in 170 clinical isolates of P. aeruginosa using population analysis profiles. The results showed that P. aeruginosa was significantly heteroresistant to meropenem (MEM), amikacin (AMK), ciprofloxacin (CIP), and ceftazidime (CAZ). The observed HR was correlated with down-regulation of QS associated genes lasI and rhlI. Further, loss-of-function analysis results showed that reduced expression of lasI and rhlI enhanced HR of P. aeruginosa to MEM, AMK, CIP, and CAZ. Conversely, overexpression of these genes or treatment with 3-oxo-C12-HSL/C4-HSL lowered HR of P. aeruginosa to the four antibiotics. Additionally, although downregulation of oprD and upregulation of efflux-associated genes was evident in heteroresistant subpopulations, their expression was not regulated by LasI and RhlI. Moreover, fitness cost measurements disclosed higher growth rates of PAO1ΔlasI and PAO1ΔrhlI in the presence of sub-MIC antibiotic as compared with that of wild-type PAO1. Our data suggest that under temporary antibiotic pressure, downregulation of QS might result in less fitness cost and promote HR of P. aeruginosa.

Strain-Induced Form Transition and Crystallization Behavior of the Transparent Polyamide.

A transparent polyamide, poly(4,4'-aminocyclohexyl methylene dodecanedicarboxylamide) (PAPACM12), was studied and characterized by in situ wide-angle X-ray diffraction (WAXD) to establish the relationship between its crystallization behavior, crystalline form transition under external fields, and macroscopic properties. During the heating process, cold crystallization occurred and increased, and there was no form transition below the melting point. During the isothermal process, PAPACM12 exhibited the same crystalline structure as that during the heating process. The crystalline structure of PAPACM12 was attributed to α-form crystal, which is the stable form, according to the WAXD diffraction peaks of the conventional AABB-type polyamides. During stretching deformation, the crystal transition from α-form to γ-form and strain-induced crystallization were observed to contribute to the PAPACM12 with higher breaking strength and elongation. This study firstly determine the crystalline structure of transparent polyamides, and then the controlled strain-induced crystallization and transformation are demonstrated to be effective preparation methods for polyamides with high properties.

Effects of lentivirus-mediated CYP17A1 gene silencing on the biological activity of glioma.

Gliomas are the most common malignant primary brain tumors with poor prognosis. We attempted to explore the role of CYP17A1 in glioma progression. We demonstrated that the expression of CYP17A1 was significantly higher in the glioma tissues than the normal brain tissues, especially in malignant glioma. Moreover, the expression of CYP17A1 gene was positively correlative with glioma pathological grades. In vitro, CYP17A1 gene silence inhibited the proliferation and invasion of glioma cells and promoted the apoptosis in glioma cells. Also, the subcutaneously transplanted tumour in BALB/C-nu showed that CYP17A1 gene silence inhibited glioma growth. These results reveal that CYP17A1 plays a major role in the progress of glioma.

G-protein-coupled receptor kinase-5 promotes glioblastoma progression by targeting the nuclear factor kappa B pathway.

G-protein-coupled receptor kinase-5 (GRK5) plays essential roles in multiple celluar events. However, its role in the development and progression of glioma is poorly understood. In this research, we found that GRK5 is significantly upregulated in human gliomas. For the first time, a close relationship was noted between GRK5 expression and blood vessel development in human glioma. Specifically co-expression of GRK5 and the tumor stem cell marker CD133 was observed in the cytoplasm of high grade glioma cells. The depletion of GRK5 suppressed the proliferation, migration and invasion in glioma cells, and promoted apoptosis. We next discovered that GRK5 knockdown inhibits the nuclear factor kappa B (NF-κB) pathway, thus resulting in downregulation of key downstream secretory products CCL2, IL-6 and IL-8 in glioma cell conditioned medium (CM). In addition, treatment of cells with the NF-κB stimulator PMA reversed this effect and increased the GRK5 level. Our results demonstrate an oncogenic role for GRK5 and reveal an activation of the GRK5-NF-κB pathway during the malignant progression of glioma.

The long non-coding RNA CRNDE acts as a ceRNA and promotes glioma malignancy by preventing miR-136-5p-mediated downregulation of Bcl-2 and Wnt2.

The colorectal neoplasia differentially expressed (CRNDE) gene encodes a long non-coding RNA (lncRNA) that is the most unregulated among 129 lncRNAs differentially expressed in gliomas. In this study, we confirmed high CRNDE expression in clinical glioma specimens and observed through experiments in human glioma cell lines a novel molecular mechanism by which CRNDE may contribute to glioma pathogenesis. By inducing or silencing CRNDE expression, we detected a positive correlation between CRNDE levels and the proliferative, migratory, and invasive capacities of glioma cells, which were concomitant with a decreased apoptosis rate. Our experiments also suggest that these effects are mediated by downregulation of miR-136-5p, which correlated with the glioma WHO grade. Based on predicted CRNDE/miR-136-5p/mRNA interactions, both the mRNA and protein expression analyses suggested that miR-136-5p-mediated repression of Bcl-2 and Wnt2 underlies the pro-tumoral actions of CRNDE. We therefore propose that CRNDE functions as a competing endogenous RNA (ceRNA) that binds to and negatively regulates miR-136-5p, thereby protecting Bcl-2 and Wnt2 from miR-136-5p-mediated inhibition in glioma.