Recent advances on thermosensitive hydrogels-mediated precision therapy.

Precision therapy has become the preferred choice attributed to the optimal drug concentration in target sites, increased therapeutic efficacy, and reduced adverse effects. Over the past few years, sprayable or injectable thermosensitive hydrogels have exhibited high therapeutic potential. These can be applied as cell-growing scaffolds or drug-releasing reservoirs by simply mixing in a free-flowing sol phase at room temperature. Inspired by their unique properties, thermosensitive hydrogels have been widely applied as drug delivery and treatment platforms for precision medicine. In this review, the state-of-the-art developments in thermosensitive hydrogels for precision therapy are investigated, which covers from the thermo-gelling mechanisms and main components to biomedical applications, including wound healing, anti-tumor activity, osteogenesis, and periodontal, sinonasal and ophthalmic diseases. The most promising applications and trends of thermosensitive hydrogels for precision therapy are also discussed in light of their unique features.

Molecular insights into chronic atrophic gastritis treatment: Coptis chinensis Franch studied via network pharmacology, molecular dynamics simulation and experimental analysis.

Chronic atrophic gastritis (CAG), characterized by inflammation and erosion of the gastric lining, is a prevalent digestive disorder and considered a precursor to gastric cancer (GC). Coptis chinensis France (CCF) is renowned for its potent heat-clearing, detoxification, and anti-inflammatory properties. Zuojin Pill (ZJP), a classic Chinese medicine primarily composed of CCF, has demonstrated effectiveness in CAG treatment. This study aims to elucidate the potential mechanism of CCF treatment for CAG through a multifaceted approach encompassing network pharmacology, molecular docking, molecular dynamics simulation and experimental verification. The study identified three major active compounds of CCF and elucidated key pathways, such as TNF signaling, PI3K-Akt signaling and p53 signaling. Molecular docking revealed interactions between these active compounds and pivotal targets like PTGS2, TNF, MTOR, and TP53. Additionally, molecular dynamics simulation validated berberine as the primary active compound of CCF, which was further confirmed through experimental verification. This study not only identified berberine as the primary active compound of CCF but also provided valuable insights into the molecular mechanisms underlying CCF's efficacy in treating CAG. Furthermore, it offers a reference for refining therapeutic strategies for CAG management.

Using Gaussian accelerated molecular dynamics combined with Markov state models to explore the mechanism of action of new oral inhibitors on Complex I.

In this study, our focus was on investigating H-1,2,3-triazole derivative HP661 as a novel and highly efficient oral OXPHOS inhibitor, with its molecular-level inhibitory mechanism not yet fully understood. We selected the ND1, NDUFS2, and NDUFS7 subunits of Mitochondrial Complex I as the receptor proteins and established three systems for comparative analysis: protein-IACS-010759, protein-lead compound 10, and protein-HP661. Through extensive analysis involving 500 ns Gaussian molecular dynamics simulations, we gained insights into these systems. Additionally, we constructed a Markov State Models to examine changes in secondary structures during the motion processes. The research findings suggest that the inhibitor HP661 enhances the extensibility and hydrophilicity of the receptor protein. Furthermore, HP661 induces the unwinding of the α-helical structure in the region of residues 726-730. Notably, key roles were identified for Met37, Phe53, and Pro212 in the binding of various inhibitors. In conclusion, we delved into the potential molecular mechanisms of triazole derivative HP661 in inhibiting Complex I. These research outcomes provide crucial information for a deeper understanding of the mechanisms underlying OXPHOS inhibition, offering valuable theoretical support for drug development and disease treatment design.

Study on the Mechanism of Interaction between Dipeptidyl Peptidase 4 and Inhibitory Peptides Based on Gaussian Accelerated Molecular Dynamic Simulation.

Dipeptidyl peptidase 4 (DPP4) inhibitors can effectively inhibit the activity of DPP4, increasing the concentrations of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which allows for them to effectively contribute to the reduction of blood sugar levels. Leu-Pro-Ala-Val-Thr-Ile-Arg (LPAVTIR) and Leu-Pro-Pro-Glu-His-Asp-Trp-Arg (LPPEHDWR) were the two peptides with the strongest inhibitory activity against DPP4 selected from silkworm pupa proteins. In this study, four systems were established: Apo (ligand-free DPP4), IPI (IPI-bound DPP4), LPAVTIR (LPAVTIR-bound DPP4), LPPEHDWR (LPPEHDWR-bound DPP4), and Gaussian accelerated molecular dynamic (GaMD) simulation was conducted to investigate the mechanism of action of two inhibitory peptides binding to DPP4. Our study revealed that the LPAVTIR peptide possessed a more stable structure and exhibited a tighter binding to the Ser630 active site in DPP4, thus exhibiting a favorable competitive inhibition effect. In contrast, the LPPEHDWR peptide caused the horizontal α-helix (residues 201-215) composed of Glu205 and Glu206 residues in DPP4 to disappear. The spatial arrangement of active sites Ser630 relative to Glu205 and Glu206 was disrupted, resulting in enzyme inactivation. Moreover, the size of the substrate channel and cavity volume was significantly reduced after the binding of the inhibitory peptide to the protein, which was an important factor in the inhibition of the enzyme activity. A similar effect was also found from IPI (our positive control). By stabilizing the active site of DPP4, the IPI peptide induced the disappearance of the horizontal α-helix and a notable reduction in the active cavity volume. In conclusion, our study provided a solid theoretical foundation for the inhibitory mechanisms of IPI, LPAVTIR, and LPPEHDWR on DPP4, offering valuable insights for advancing the development of drug targets for type 2 diabetes.

Pediatric paragonimiasis: a retrospective analysis of cases from a county in south-west China.

Introduction: The clinical manifestations of paragonimiasis are diverse and non-specific, and can easily lead to misdiagnosis. We aimed to analyze the clinical manifestations, laboratory features, treatment, and clinical outcome of children with paragonimiasis in order to improve recognition of this disease and avoid misdiagnosis. Methods: Children diagnosed with paragonimiasis from August 2016 to July 2022 were included in the study. Information on population informatics, medical history, and laboratory features was extracted from case data. The clinical features of paragonimiasis were retrospectively analyzed. Results: A total of 45 children were included in this study. All children had, at least, one risk factor. The clinical features mainly included fever, cough, pleural effusion, peritoneal effusion, and subcutaneous nodules. The main imaging findings were alveolar exudation, peritoneal effusion, pleural thickening, and local nodules. The "tunnel sign" finding on computed tomography (CT)/magnetic resonance imaging (MRI) was helpful in establishing the diagnosis of paragonimiasis. After praziquantel treatment, most of the children improved, and one child with cerebral paragonimiasis experienced sequelae. Conclusion: Most children with paragonimiasis have a good prognosis, but few children can experience sequelae. Avoidance of untreated water and raw food is a simple, feasible, and effective preventive measure.

Au nanocluster-modulated macrophage polarization and synoviocyte apoptosis for enhanced rheumatoid arthritis treatment.

The persistent progression of synovial inflammation and cartilage destruction contributes to the crosstalk between pro-inflammatory macrophages and activated fibroblast-like synoviocytes (FLSs) in a synovial microenvironment. In this work, structurally well-defined Au25 nanoclusters were synthesized to induce phenotypic polarization of pro-inflammatory macrophages and apoptosis of activated FLSs for enhanced rheumatoid arthritis treatment. These ultra-small nanoclusters significantly modulated phenotypic polarization of a pro-inflammatory M1 phenotype to an anti-inflammatory phenotype M2 for relieving inflammation. Additionally, Au25 nanoclusters can efficiently activate reactive oxygen species (ROS)-mediated apoptotic signaling pathways by inactivating thioredoxin reductase (TrxR), resulting in imbalance of the cellular redox homeostasis and initiation of FLS apoptosis. In an adjuvant-induced arthritis rat model, Au25 nanoclusters efficiently ameliorated the hyperplasia of the synovium and reduced inflammatory cell infiltration with negligible side effects. This study provided a new insight into Au nanoclusters for treating rheumatoid arthritis.

Combining Dual-Light Emissions to Achieve Efficient Broadband Yellowish-Green Luminescence in One-Dimensional Hybrid Lead Halides.

In recent years, low-dimensional lead halides have emerged as some of most attractive photoelectric materials due to their intrinsic broadband emissions with a potential application in white-light emitting diodes. To achieve the desired performance, tremendous research has emphasized the modulation of inorganic components as optical centers; however, less work has paid attention to the direct contribution of the organic components. Herein, we successfully assembled two new hybrid lead halides of [H2BPP]Pb2X6 (X = Br, 1, and Cl, 2) containing one-dimensional double [Pb2X6]2- chains using optically active 1,3-bis(4-pyridyl)-propane (BPP) as an organic cation. Under UV-light excitation, compounds 1 and 2 exhibit broadband yellowish-green emissions, which were verified by promising photoluminescence quantum efficiencies (PLQEs) of 8.10% and 4.84%, respectively. The broadband light emissions are derived from the combination of dual higher-energy blue and lower-energy yellow light spectra, which can be attributed to the individual contributions of the organic and inorganic components, respectively, according to the time-resolved and temperature-dependent emission spectra as well as theoretical calculations. This work proves the great contribution of organic components to the photophysical properties and provides a new design strategy to realize broadband light emission by rationally combining the dual-emitting properties of different assembly blocks.

Long non-coding RNA SNHG6 promotes the growth and invasion of non-small cell lung cancer by downregulating miR-101-3p.

BACKGROUND: The aim of this study was to determine the function of long non-coding RNA small nucleolar RNA host gene 6 (SNHG6) in non-small cell lung cancer (NSCLC) and its underlying mechanisms. METHODS: The association of SNHG6 or miR-101-3p with clinicopathological characteristics and prognosis in patents with NSCLC was assessed by TCGA dataset. Cell proliferation and invasion were evaluated by MTT and Transwell assays and SNHG6-specific binding with miR-101-3p was verified by bioinformatic analysis, luciferase gene report and RNA immunoprecipitation assays. qRT-PCR and Western blot was used to assess the effects of SNHG6 on the expression of miR-101-3p and chromodomain Y like (CDYL) in NSCLC cells. A xenograft tumor model in vivo was established to observe the effects of SNHG6 knockdown on tumor growth. RESULTS: We found that increased expression of SNHG6 was associated with pathological stage and lymph node infiltration, and acted as an independent prognostic factor of tumor recurrence in patients with NSCLC. Silencing SNHG6 expression repressed cell growth and invasion in vitro and in vivo, but overexpression of SNHG6 reversed these effects. Furthermore, SNHG6 was identified to act as a sponge of miR-101-3p, which could reduce cell proliferation and attenuate SNHG6-induced CDYL expression. Low expression of miR-101-3p or high expression of CDYL was related to poor survival in patients with NSCLC. CONCLUSIONS: Our findings demonstrated that lncRNA SNHG6 contributed to the proliferation and invasion of NSCLC by downregulating miR-101-3p.

Dyspnea after thyroidectomy induced by intratracheal lymphoma: A case report.

The aim of the present study was to report a rare case of dyspnea caused by rapid growth of intratracheal lymphoma in the 2 weeks following thyroid surgery. A 53-year-old male patient underwent a right thyroidectomy due to tracheal compression by a mass of the right thyroid lobe. However, 2 weeks after the surgery, the patient developed dyspnea, which was managed by tracheotomy. An urgent computed tomography scan revealed that the soft tissue of the upper trachea was significantly thickened compared with prior to surgery, resulting in narrowing of the airway. Postoperative pathology revealed right thyroid lymphoma, and the final diagnosis was intratracheal lymphoma. The intratracheal mass regressed after chemotherapy combined with rituximab. We herein review the diagnostic and treatment process of this case of dyspnea, and analyze the outcome, in order to provide a reference for the timely diagnosis and treatment of patients developing dyspnea following thyroid surgery.

Efficacy of Endovascular Radiofrequency Ablation for Thromboangiitis Obliterans (Buerger's Disease).

BACKGROUND: This study aimed to evaluate the efficacy of endovascular radiofrequency ablation (RFA) for the treatment of thromboangiitis obliterans (TAO). METHODS: Total 30 males (median age: 46.00 years, interquartile range: 42.00-51.25 years) with unilateral TAO in the lower extremity underwent RFA were retrospectively enrolled from January 2013 and October 2013. The pre-operative and post-operative digital subtraction angiographic (DSA) images were recorded. Pain scores preoperatively and postoperatively were assessed according to the World Health Organization Pain Guideline. The values of ankle brachial index (ABI) at pre-operation, post-operation, 2 weeks and 2 years after surgery were all recorded and analyzed. Additionally, a 2-year follow up was performed by a computed tomographic angiography (CTA) image. RESULTS: The DSA images indicated that occlusion of femoral artery was improved after surgery. Moreover, there was no recurrence of TAO at 2 years of follow-up based on the CTA images. The pain score (P < 0.001) was significantly deceased after surgery. The values of ABI at postoperation, 2 weeks after surgery, and 2 years after surgery were all significantly higher than the preoperative ABI (P < 0.001). Furthermore, the values of ABI at 2 weeks after surgery and 2 years after surgery were all significantly higher than the postoperative ABI (P < 0.001). CONCLUSIONS: These results supported the application of endovascular RFA for treating TAO.

Microarray Analysis of Long Non-coding RNA Expression Profile Associated with 5-Fluorouracil-Based Chemoradiation Resistance in Colorectal Cancer Cells.

BACKGROUND: Preoperative 5-fluorouracil (5-FU)-based chemoradiotherapy is a standard treatment for locally advanced colorectal cancer (CRC). However, CRC cells often develop chemoradiation resistance (CRR). Recent studies have shown that long non-coding RNA (lncRNA) plays critical roles in a myriad of biological processes and human diseases, as well as chemotherapy resistance. Since the roles of lncRNAs in 5-FU-based CRR in human CRC cells remain unknown, they were investigated in this study. MATERIALS AND METHODS: A 5-FU-based concurrent CRR cell model was established using human CRC cell line HCT116. Microarray expression profiling of lncRNAs and mRNAs was undertaken in parental HCT116 and 5-FU-based CRR cell lines. RESULTS: In total, 2,662 differentially expressed lncRNAs and 2,398 mRNAs were identified in 5-FU-based CRR HCT116 cells when compared with those in parental HCT116. Moreover, 6 lncRNAs and 6 mRNAs found to be differentially expressed were validated by quantitative real time PCR (qRT-PCR). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for the differentially expressed mRNAs indicated involvement of many, such as Jak- STAT, PI3K-Akt and NF-kappa B signaling pathways. To better understand the molecular basis of 5-FU-based CRR in CRC cells, correlated expression networks were constructed based on 8 intergenic lncRNAs and their nearby coding genes. CONCLUSIONS: Changes in lncRNA expression are involved in 5-FU-based CRR in CRC cells. These findings may provide novel insight for the prognosis and prediction of response to therapy in CRC patients.

Parecoxib: an enhancer of radiation therapy for colorectal cancer.

BACKGROUND: To study the effect of parecoxib, a novel cyclooxygenase-2 selective inhibitor, on the radiation response of colorectal cancer (CRC) cells and its underlying mechanisms. MATERIALS AND METHODS: Both in vitro colony formation and apoptosis assays as well as in vivo mouse xenograft experiments were used to explore the radiosensitizing effects of parecoxib in human HCT116 and HT29 CRC cells. RESULTS: Parecoxib sensitized CRC cells to radiation in vitro with a sensitivity enhancement ratio of 1.32 for HCT116 cells and 1.15 for HT29 cells at a surviving fraction of 0.37. This effect was partially attributable to enhanced apoptosis induction by parecoxib combined with radiation, as illustrated using an in vitro apoptosis assays. Parecoxib augmented the tumor response of HCT116 xenografts to radiation, achieving growth delay more than 20 days and an enhancement factor of 1.53. In accordance with the in vitro results, parecoxib combined with radiation resulted in less proliferation and more apoptosis in tumors than radiation alone. Radiation monotherapy decreased microvessel density (MVD) and microvessel intensity (MVI), but increased the hypoxia level in xenografts. Parecoxib did not affect MVD, but it increased MVI and attenuated hypoxia. CONCLUSIONS: Parecoxib can effectively enhance radiation sensitivity in CRC cells through direct effects on tumor cells and indirect effects on tumor vasculature.

Increased levels of ß-catenin, LEF-1, and HPA-1 correlate with poor prognosis for acral melanoma with negative BRAF and NRAS mutation in BRAF exons 11 and 15 and NRAS exons 1 and 2.

To determine the expression of ß-catenin, lymphoid enhancer-binding protein-1 (LEF-1), and heparanase-1 (HPA-1) and to evaluate these proteins' potential prognostic values in malignant acral melanoma without mutations in BRAF exons 11 and 15 and NRAS exons 1 and 2, specimens from 90 patients with wild-type BRAF and NRAS were assessed and analyzed by immunohistochemistry and western blotting. The positive expression of ß-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 was observed in 36 (72%), 31 (62%), and 32 (64%) of the detected acral melanomas, respectively. The expression of ß-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 was not correlated with gender, age, or diseased body parts (p>0.05), but was significantly positively correlated with the tumor node metastasis (TNM) stage and metastasis (correlation=0.406 and 0.716, 0.397 and 0.582, 0.353 and 0.579; p=0.040 and 0.0001, 0.0040 and 0.0001, 0.0120 and 0.0001, respectively). We also observed that the increased expression of ß-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 was significantly correlated with decreased survival and poor prognosis (p=0.001, 0.010, and 0.023, respectively). A multifactorial analysis using Cox's regression model revealed that ß-catenin, lymphoid enhancer-binding protein-1, heparanase-1, and the TNM stage were all independent factors in malignant melanoma (risk ratios were 7.294, 5.550, 5.622, and 4.794; p-values were 0.007, 0.018, 0.018, and 0.029, respectively). This study may provide the basis for the use of ß-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 as novel targets in the treatment of malignant invasion and metastasis in acral melanoma cancer. The expression of ß-catenin, LEF-1, and HPA-1 was assessed and compared in malignant melanoma with that of peritumoral tissue and benign nevus in the patients with negative mutations in BRAF exons 11 and 15 and NRAS exons 1 and 2. The study may provide the basis for ß-catenin, LEF-1, and HPA-1 as new targets in the treatment of malignant invasion and metastasis in melanoma cancer.

[Levels of activation markers of platelets in peripheral blood and their significance in patients with lung cancer].

BACKGROUND: Platelet activation often occurs in intermediate and advanced tumors, with increases of expression and release of platelet adhesion molecule. The aim of this study is to investigate the expression of activation markers of platelet and their significance in lung cancer. METHODS: The activation markers of platelet, CD62P and CD63, were detected in peripheral blood of 120 patients with lung cancer and 60 healthy persons by FCM method. RESULTS: The levels of peripheral blood CD62P and CD63 of lung cancer patients were significantly higher than those of healthy people (P < 0.01). In lung cancer group, the levels of peripheral blood CD62P and CD63 on the seventh postoperative day were significantly lower than those before operation and on the first postoperative day (P < 0.01). The levels of peripheral blood CD62P and CD63 before operation were closely related to size of tumor, lymph node status and TNM stages (P < 0.01), but not to cell differentiation, histology, age and sex of lung cancer patients (P > 0.05). CONCLUSIONS: Activation markers of platelet obviously increase in peripheral blood of lung cancer patients and they may play important roles in tumor growth and lymphatic metastasis. The levels of activation markers of platelet may be useful predictors for prognosis.

[Inhibitory effect of Periplaneta Americana extract on 3LL lung cancer in mice].

BACKGROUND: It has been known that Kangfuxin, a drug derived from Periplaneta Americana, can induce cell apoptosis of many cancer cell lines in vitro. The aim of this study is to investigate the inhibitory effect and mechanism of Periplaneta Americana extract (PAE) on 3LL lung cancer in mice. METHODS: The C57BL/6J mice transplanted with 3LL lung cancer were divided into normal saline (NS), PAE high dose (PAE-H) and PAE low dose (PAE-L) groups. The body weight changes and inhibitory rate of tumor growth in each group were observed. In addition, the cell cycle, apoptosis index (AI) and the expression of apoptosis associated genes were analysed by flow cytometry (FCM). RESULTS: The body weights were decreased in PAE-L and PAE-H treated group compared with NS group and the inhibitive rate of tumor growth was 41.24% and 81.08% respectively. FCM assay indicated that PAE could induce apoptosis of lung cancer cell, and the apoptosis rate was concentration-dependent. At the same time, the number of S and G2/M phase cells was decreased, most of the cells were arrested in G1/G1 phase. The result of TUNEL showed that there were apoptosis and necrosis associated with upregulated expression of Fas, FasR and p53 genes, and downregulated expression of Bcl-2. CONCLUSIONS: PAE may inhibit the growth of 3LL lung cancer in mice and induce apoptosis of 3LL lung cancer cells. It might be related to its effects on the regulation of apoptotic gene expression.