Multifunctional nanogel loaded with cerium oxide nanozyme and CX3CL1 protein: Targeted immunomodulation and retinal protection in uveitis rat model.

Effectively addressing retinal issues represents a pivotal aspect of blindness-related diseases. Novel approaches involving reducing inflammation and rebalancing the immune response are paramount in the treatment of these conditions. This study delves into the potential of a nanogel system comprising polyethylenimine-benzene boric acid-hyaluronic acid (PEI-PBA-HA). We have evaluated the collaborative impact of cerium oxide nanozyme and chemokine CX3CL1 protein for targeted immunomodulation and retinal protection in uveitis models. Our nanogel system specifically targets the posterior segment of the eyes. The synergistic effect in this area reduces oxidative stress and hampers the activation of microglia, thereby alleviating the pathological immune microenvironment. This multifaceted drug delivery system disrupts the cycle of oxidative stress, inflammation, and immune response, suppressing initial immune cells and limiting local retinal structural damage induced by excessive immune reactions. Our research sheds light on interactions within retinal target cells, providing a promising avenue for the development of efficient and innovative drug delivery platforms.

Emerging roles of PHLPP phosphatases in lung cancer.

Pleckstrin homologous domain leucine-rich repeating protein phosphatases (PHLPPs) were originally identified as protein kinase B (Akt) kinase hydrophobic motif specific phosphatases to maintain the cellular homeostasis. With the continuous expansion of PHLPPs research, imbalanced-PHLPPs were mainly found as a tumor suppressor gene of a variety of solid tumors. In this review, we simply described the history and structures of PHLPPs and summarized the recent achievements in emerging roles of PHLPPs in lung cancer by 1) the signaling pathways affected by PHLPPs including Phosphoinositide 3-kinase (PI3K)/AKT, RAS/RAF/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and Protein kinase C (PKC) signaling cascades. 2) function of PHLPPs regulatory factor USP46 and miR-190/miR-215, 3) the potential roles of PHLPPs in disease prognosis, Epidermal growth factor receptors (EGFR)- tyrosine kinase inhibitor (TKI) resistance and DNA damage, 4) and the possible function of PHLPPs in radiotherapy, ferroptosis and inflammation response. Therefore, PHLPPs can be considered as either biomarker or prognostic marker for lung cancer treatment.

TREM-1 as a potential prognostic biomarker associated with immune infiltration in clear cell renal cell carcinoma.

BACKGROUND: The tumor immune microenvironment plays a crucial role in the efficacy of various therapeutics. However, their correlation is not yet completely understood in Clear cell renal cell carcinoma (ccRCC). This study aimed to investigate the potential of TREM-1 as a potential novel biomarker for ccRCC. METHODS: We constructed a ccRCC immune prognostic signature. The clinical characteristics, the status of the tumor microenvironment, and immune infiltration were analyzed through the ESTIMATE and CIBERSORT algorithms for the hub gene, while the Gene Set Enrichment Analysis and PPI analysis were performed to predict the function of the hub gene. Immunohistochemical staining was used to detect the expression of TREM-1 in renal clear cell carcinoma tissues. RESULTS: The CIBERSORT and ESTIMATE algorithms revealed that TREM-1 was correlated with the infiltration of 12 types of immune cells. Therefore, it was determined that TREM-1 was involved in numerous classical pathways in the immune response via GSEA analysis. In Immunohistochemical staining, we found that the expression of TREM-1 was significantly upregulated with increasing tumor grade in renal clear cell carcinoma, and elevated TREM-1 expression was associated with poor prognosis. CONCLUSIONS: The results suggest that TREM-1 may act as an implicit novel prognostic biomarker in ccRCC that could be utilized to facilitate immunotherapeutic strategy.

Penetrating-peptide-mediated non-invasive Axitinib delivery for anti-neovascularisation.

The unique physiological makeup of the eye limits the use of small-molecule drugs for treating the posterior segment of the eye. Nevertheless, transmembrane-peptide-mediated non-invasive drug delivery can serve as an ideal treatment strategy, as it is capable of delivering small-molecule drugs across the membrane in the form of eye drops, thereby achieving the effective treatment of neovascularisation in the posterior cavity. In this study, we screened and compared the posterior segment distribution of two poly(ethylene glycol)-distearoylphosphatidylethanolamine carriers modified using targeting-peptides. Thereafter, a transmembrane peptide (i.e., PENE) with a greater ability of transmembrane delivery was selected for delivering the anti-vascular drug (i.e., Axitinib) to the posterior segment of the eye. Using two different mouse models with fundus neovascular diseases, the complete non-invasive delivery of Axitinib to the posterior segment of the eye was confirmed using the targeted system; the designed eye drops (i.e., PENE-nanoparticles) could achieve drug distribution to the retina and veins of the eye as well as good drug permeability for renewal. Moreover, using the eye-drop treatment, neovascularisation was substantially reduced, demonstrating the high efficacy of this drug delivery system. This study, which combines nanodrug-loading technology and the transmembrane delivery of penetrating-peptides to achieve the goal of the non-invasive delivery of small-molecule drugs through the dense blood vessels of the sclera, shows wide applicability and considerably expands the use of ocular drugs. Thus, this study is expected to help develop a more acceptable drug administration strategy for the drug treatment of the posterior segment of the eye.

Amlodipine Improves Spinal Cord Injury Repair by Inhibiting Motoneuronal Apoptosis Through Autophagy Upregulation.

STUDY DESIGN: The effect of amlodipine (AM) on spinal cord injury (SCI) and autophagy was researched by establishing ventral spinal cord cells (VSC4.1) oxygen and glucose deprivation model and SCI mice model. OBJECTIVE: To determine the neuroprotective effects of AM by upregulating autophagy during SCI repair. SUMMARY OF BACKGROUND DATA: AM, an antihypertensive medication, has been shown in several studies to inhibit neuronal apoptosis and exert neuroprotective effects in various central nervous system diseases. However, its effects on SCI are unexplored. Autophagy could inhibit cell apoptosis, which has been shown to promote SCI repair. However, the role of AM in autophagy remains unclear. METHODS: We examined the relationship between AM, apoptosis, and autophagy in ventral spinal cord cells and the injured spinal cords of C57BL/6 female mice respectively, following histological, behavioral, microscopic, immunofluorescence, and western blotting analyses. RESULTS: We found that AM could inhibit motor neuronal apoptosis in vitro. Furthermore, AM promoted locomotor recovery by upregulating autophagy and alleviating apoptosis, neuronal loss, and spinal cord damage after SCI. CONCLUSION: AM inhibited motoneuronal apoptosis by upregulating autophagy to improve SCI recovery.

Prognostic factors for postoperative survival in melanoma patients with bone metastasis.

ABSTRACT: Melanoma can spread to the bone by metastasis and is relevant to a poor outcome. However, because of the rarity of melanoma patients with bone metastasis, the prognostic postoperative survival factors of them have not been elucidated. The aim of this special population-based cohort was to elucidate the prognostic factors associated with postoperative survival. The Surveillance, Epidemiology, and End Results database was used to extract postoperative survival data relating to patients with melanoma and bone metastasis at diagnosis between 2010 and 2016, along with data on a range of potential postoperative prognostic factors. We then investigated the potential postoperative prognostic roles of these factors using a Cox regression model and the Kaplan-Meier analysis. In all, the Surveillance, Epidemiology, and End Results database included 186 cases. Regarding overall survival, the 1-, 3-, and 5-year overall survival rates for the entire cohort were 36.2%, 15.4%, and 9.5%, respectively. Regarding cancer-specific survival, the 1-, 3-, and 5-year cancer-specific survival rates were 42.0%, 23.2%, and 16.6%, respectively. Within a cohort of melanoma patients with bone metastasis after surgery, our analysis showed that a smaller tumor size and the lack of metastases at other sites were predictors of survival.

Chemokines in bone-metastatic breast cancer: Therapeutic opportunities.

Due to non-response to chemotherapy, incomplete surgical resection, and resistance to checkpoint inhibitors, breast cancer with bone metastasis is notoriously difficult to cure. Therefore, the development of novel, efficient strategies to tackle bone metastasis of breast cancer is urgently needed. Chemokines, which induce directed migration of immune cells and act as guide molecules between diverse cells and tissues, are small proteins indispensable in immunity. These complex chemokine networks play pro-tumor roles or anti-tumor roles when produced by breast cancer cells in the tumor microenvironment. Additionally, chemokines have diverse roles when secreted by various immune cells in the tumor microenvironment of breast cancer, which can be roughly divided into immunosuppressive effects and immunostimulatory effects. Recently, targeting chemokine networks has been shown to have potential for use in treatment of metastatic malignancies, including bone-metastatic breast cancer. In this review, we focus on the role of chemokines networks in the biology of breast cancer and metastasis to the bone. We also discuss the therapeutic opportunities and future prospects of targeting chemokine networks, in combination with other current standard therapies, for the treatment of bone-metastatic breast cancer.

Triptolide improves spinal cord injury by promoting autophagy and inhibiting apoptosis.

We investigated the effect of triptolide (TP) on spinal cord injury (SCI), and its underlying mechanism. Following the establishment of the SCI model using YFP H-line transgenic mice, TP was intraperitoneally injected at a dose of 0.2 mg/kg once daily for 7 days. Behavioral tests, Nissl staining, and hematoxylin-eosin staining were employed to assess motor function recovery and neuronal cell death. Western blot and immunofluorescence staining were used to assess autophagy-associated proteins (LC3B, p62, Beclin-1) and the apoptosis-associated proteins (Bcl-2, caspase-3, Bax). The TP-treated group showed improved motor functions, and reduced neuronal cell death. Also, significant upregulation of Bcl-2 and LC3B expressions, with the downregulation of p62, Bax and caspase-3 expressions were found in the TP-treated group. Additionally, phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1 and ERK2) was decreased in the TP-treated group. TP mediates its protective effect in SCI by promoting the autophagic pathway while inhibiting the MAPK/ERK1/2 signaling pathway. These results demonstrate the therapeutic potential of TP in SCI.