Background: 5-Fluorouracil (5-FU) is the first-choice treatment for all grades of gastric carcinoma, one of the most common malignant digestive tract tumors worldwide. However, the resistance to 5-FU is a major problem affecting the treatment and prognosis of gastric cancer. As a monomer component of Chinese traditional herbs, tetrandrine has high efficiency, low toxicity, multitarget effects, and strong specificity, and can reverse multidrug resistance by several pathways. Organoid technology is a versatile tool for the generation and long-term maintenance of near-native three-dimensional epithelial tissues in vitro, and the generation of cancer organoids from primary patient material enables testing many therapeutic agents in the resulting organoid cultures. This article aims to build GCOs and explore the potential of tetrandrine to overcome drug resistance and the associated signaling pathways by organoid technology.Methods: The typical GC tumor fractions far away from necrotic areas were obtained by surgery. Genomic analysis, histology and imaging, and multiplex immunofluorescence were performed. Meanwhile, the GCOs were constructed and were cultured for six months. The GCOs retained histopathological features and drug reactivity of the primary tumor. To study the reversal and sensitization effect of tetrandrine on 5-FU resistance, 5-FU–resistant cell lines were constructed. Through whole-exon sequencing of two cell lines with different sensitivities, the related genes that may cause drug resistance were screened out. The protein levels in two cell lines were quantified using Western blot (WB) analysis.Findings: The patients’ resistance to 5-FU was reproduced at the organoid level, and tetrandrine improved the sensitivity of GCOs to 5-FU. In the MN-45 gastric cancer cell line, tetrandrine significantly improved the cell-killing effect of 5-FU. We found that the TGF-β signaling pathway and ABCB1 transporters were the main causes of drug resistance in gastric cancer. Tetrandrine can enhance the sensitivity of tumor cells to 5-FU by inhibiting the TGF-β signaling pathway and increasing the expression of ABCB1 transporter.Interpretation: Tetrandrine can enhance the sensitivity of tumor cells to 5-FU by inhibiting the TGF-β signaling pathway and increasing the expression of ABCB1 transporter.Funding: This work was not supported by any research project.Declaration of Interest: The authors declare no potential conflicts of interest.Ethical Approval: All experiments involving human tissue specimens were approved by the Ethics Committee of China-Japan Friendship Hospital (approved number is 2022-KY-228-1), and informed consent were obtained from all participating patients.
Background The increasing maturity of sequencing technology provides a convenient approach to studying the role of skin microorganisms in acne pathogenesis. However, there are still too few studies about the skin microbiota of Asian acne patients, especially a lack of detailed analysis of the characteristics of the skin microbiota in the different acne sites. Methods In this study, a total of 34 college students were recruited and divided into the health, mild acne, and severe acne groups. The bacterial and fungal flora of samples were separately detected by 16S and 18S rRNA gene sequencing. The biomarkers of different acne grades and different acne sites [forehead, cheek, chin, torso (including chest and back)] were excavated. Results and Discussion Our results indicated that there was no significant difference in species diversity between groups. The genera like Propionibacterium, Staphylococcus, Corynebacterium , and Malassezia , which have a relatively high abundance in the skin microbiota and were reported as the most acne-associated microbes, were no obvious differences between groups. On the contrary, the abundance of less reported Gram-negative bacteria ( Pseudomonas , Ralstonia , and Pseudidiomarina ) and Candida has a significant alteration. Compared with the health group and the mild group, in the severe group, the abundance of Pseudomonas and Ralstonia sharply reduced while that of Pseudidiomarina and Candida remarkably raised. Moreover, different acne sites have different numbers and types of biomarkers. Among the four acne sites, the cheek has the greatest number of biomarkers including Pseudomonas , Ralstonia , Pseudidiomarina , Malassezia , Saccharomyces , and Candida , while no biomarker was observed for the forehead. The network analysis indicated that there might be a competitive relationship between Pseudomonas and Propionibacterium . This study would provide a new insight and theoretical basis for precise and personalized acne microbial therapy.
Tellurium (Te) nanomaterials (NMs) have emerged as a new antibacterial candidate to respond to the complex global health challenge of bacterial resistance. Herein, Te nanoneedles (NNs) that act both chemically and physically on bacteria are synthesized by a facile method using Na2TeO3, urea and glucose. It is found that the prepared Te NNs have a strong affinity to the cell membrane of bacteria and subsequently promote the generation of reactive oxygen species (ROS) in bacteria, resulting in an excellent antibacterial effect toward Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative). What's more, this needle-like morphology also can physically damage the bacterial cell membranes. The Te NNs per se are inert in mammalian cells to produce ROS at a proper concentration, indicating considerable biocompatibility of this material. As a proof-of-concept, the antibacterial Te NNs were used as an anti-inflammatory reagent for promoting bacteria-infected wound healing in vivo, during which Te NNs caused no evident side effects to major organs in mice. Additionally, the antibacterial activity is maintained in the presence of surface oxidation of Te NNs after long-term dispersion in phosphate buffered saline solution. The needle-like Te NMs with long-term antibacterial stability and good biocompatibility have great potential for the treatment of associated infectious diseases.
Abstract Objectives: The study aims to determine the clinical significance of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), TC/HDL-c, TG/HDL-c, and LDL-c/ HDL-c in axial spondyloarthritis (axSpA) patients. Methods: Two hundred and five axSpA patients and 71 healthy subjects were enrolled. AxSpA patients were further divided into remission group and active group. The laboratory data were collected. Spearman’s correlation, receiver operation characteristic (ROC) curves, and binary logistic regression analysis were conducted. Results: TC, TG, LDL-c and HDL-c were lower in axSpA group, while LDL-c/HDL-c was higher ( P <0.05). ROC curves results revealed that the AUC value of HDL-c for axSpA was 0.752 (CI95%: 0.693-0.811), yielding the highest AUC value. HDL-c was negatively correlated with BASDAI, CRP, and ESR ( P <0.05). TC/HDL-c was positively correlated with BASDAI, BASFI, CRP, and ESR ( P <0.05). Besides, TC/HDL-c, CRP, and ESR in axSpA of active group were higher than those in remission group, while HDL-c was lower ( P <0.05). ROC curves results showed that the AUC value of TC/HDL-c and CRP for axSpA of active group were 0.616 (CI95%: 0.539-0.694) and 0.632 (CI95%: 0.554-0.710), yielding higher AUC value than other parameters. The optimal cutoff value of TC/HDL-c for axSpA of active group was 4.218, with a Youden index of 0.195, a sensitivity of 50.6%, and a specificity of 68.9%. Binary logistic regression analysis indicated that TC/HDL-c was an independent indicator for axSpA disease activity. Conclusions: TC/HDL-c was elevated in axSpA of active group, yielding a high diagnostic value and showing a positively correlation with the disease activity of axSpA. TC/HDL-c may be a novel and reliable indicator for axSpA disease activity.
Lumbar disk herniation (LDH) with discogenic low back pain and sciatica is a common and complicated musculoskeletal disorder. The underlying mechanisms are poorly understood, and there are no effective therapies for LDH-induced pain. In the present study, we found that the patients who suffered from LDH-induced pain had elevated plasma methylglyoxal (MG) levels. In rats, implantation of autologous nucleus pulposus (NP) to the left lumbar 5 spinal nerve root, which mimicked LDH, induced mechanical allodynia, increased MG level in plasma and dorsal root ganglion (DRG), and enhanced the excitability of small DRG neurons (<30 μm in diameter). Intrathecal injection of MG also induced mechanical allodynia, and its application to DRG neurons ex vivo increased the number of action potentials evoked by depolarizing current pulses. Furthermore, inhibition of MG accumulation by aminoguanidine attenuated the enhanced excitability of small DRG neurons and the mechanical allodynia induced by NP implantation. In addition, NP implantation increased levels of advanced glycation end products (AGEs) in DRG, and intrathecal injection of MG-derived AGEs induced the mechanical allodynia and DRG neuronal hyperactivity. Intrathecal injection of MG also significantly increased the expression of AGEs in DRG. Importantly, scavenging of MG by aminoguanidine also attenuated the increase in AGEs induced by NP implantation. These results suggested that LDH-induced MG accumulation contributed to persistent pain by increasing AGE levels. Thus generation of AGEs from MG may represent a target for treatment of LDH-induced pain.
The TetR family of transcriptional regulators (TFRs), serving as crucial regulators of diverse cellular processes, undergo conformational changes induced by small-molecule ligands, which either inhibit or activate them to modulate target gene expression. Some ligands of TFRs in actinomycetes and their regulatory effects have been identified and studied; however, regulatory mechanisms of the TetR family in the lincomycin-producing Streptomyces lincolnensis remain poorly understood.
Objective: With the rising prevalence of diabetes worldwide, increased attention is focused on natural drug candidates that can treat diabetes with high efficacy but without undesired side effects. Lentinus edodes is an edible and medicinal fungus, whose polysaccharides are one of the main components that have been reported to have hypoglycemic ability. However, the detailed underlying hypoglycemic mechanism of Lentinus edodes polysaccharides is still unknown. In this study, we extracted and prepared a novel polysaccharide from Lentinus edodes, which was named LNT-1. Methods: The aim of this study was to evaluate the hypoglycemic effect of LNT-1 on mice with type 2 diabetes that was induced by a high fat and high sugar diet and streptozotocin. To explore the possible mechanism, metabolomics analysis based on UPLC-Q-TOF/MS and molecular methods were performed. Results: Data showed that treatment with LNT-1 could ameliorate the damage in diabetic mice, including physiological and biochemical indexes, oxidative parameters and histopathological changes. Moreover, 36 potential biomarkers were screened using metabolomics analysis based on UPLC-Q-TOF/MS. Among them, the main metabolic pathways were glycerophospholipid metabolism, arachidonic acid metabolism and arginine biosynthesis, thereby suggesting that oxidative stress may be involved in the occurrence of diabetes. Both the mRNA and protein expression of the Nrf2/HO-1 signaling pathway was upregulated after treatment with LNT-1, indicating that the hypoglycemic effect of LNT-1 may be related to the activation of the Nrf2/HO-1 pathway. Conclusion: LNT-1 may be a potential natural drug candidate for the prevention and treatment of diabetes by regulating the oxidative stress response. Our study aimed to provide new insights into the application of Lentinus edodes and its polysaccharide as a drug candidate and as an active ingredient in functional foods.
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