Oridonin alleviates hyperbilirubinemia through activating LXRα-UGT1A1 axis.

Hyperbilirubinemia is a serious hazard to human health due to its neurotoxicity and lethality. So far, successful therapy for hyperbilirubinemia with fewer side effects is still lacking. In this study, we aimed to clarify the effects of oridonin (Ori), an active diterpenoid extracted from Rabdosia rubescens, on hyperbilirubinemia and revealed the underlying molecular mechanism in vivo and in vitro. Here, we showed that liver X receptor alpha (LXRα) deletion eliminated the protective effect of Ori on phenylhydrazine hydrochloride-induced hyperbilirubinemia mice, indicating that LXRα acted as a key target for Ori treatment of hyperbilirubinemia. Ori significantly increased the expression of LXRα and UDP-glucuronosyltransferase 1A1 (UGT1A1) in the liver of wild-type (WT) mice, which were lost in LXRα-/- mice. Ori or LXR agonist GW3965 also reduced lipopolysaccharide/D-galactosamine-induced hyperbilirubinemia via activating LXRα/UGT1A1 in WT mice. Liver UGT1A1 enzyme activity was elevated by Ori or GW3965 in WT mice. Further, Ori up-regulated LXRα gene expression, increased its nuclear translocation and stimulated UGT1A1 promoter activity in HepG2 cells. After silencing LXRα by siRNA, Ori-induced UGT1A1 expression was markedly reduced in HepG2 cells and primary mouse hepatocytes. Taken together, Ori stimulated the transcriptional activity of LXRα, resulting in the up-regulation of UGT1A1. Therefore, Ori or its analogs might have the potential to treat hyperbilirubinemia-related diseases through modulating LXRα-UGT1A1 signaling.

A Review on Rail Defect Detection Systems Based on Wireless Sensors.

Small defects on the rails develop fast under the continuous load of passing trains, and this may lead to train derailment and other disasters. In recent years, many types of wireless sensor systems have been developed for rail defect detection. However, there has been a lack of comprehensive reviews on the working principles, functions, and trade-offs of these wireless sensor systems. Therefore, we provide in this paper a systematic review of recent studies on wireless sensor-based rail defect detection systems from three different perspectives: sensing principles, wireless networks, and power supply. We analyzed and compared six sensing methods to discuss their detection accuracy, detectable types of defects, and their detection efficiency. For wireless networks, we analyzed and compared their application scenarios, the advantages and disadvantages of different network topologies, and the capabilities of different transmission media. From the perspective of power supply, we analyzed and compared different power supply modules in terms of installation and energy harvesting methods, and the amount of energy they can supply. Finally, we offered three suggestions that may inspire the future development of wireless sensor-based rail defect detection systems.

Oridonin alleviates d-GalN/LPS-induced acute liver injury by inhibiting NLRP3 inflammasome.

Acute liver injury (ALI) is a serious syndrome that is associated with high mortality, but there are few effective treatments. The activation of NLRP3 inflammasome is associated with ALI. Oridonin is a natural substance with an anti-inflammatory effect and has been reported to be an inhibitor of NLRP3. The aim of this study was to investigate the protective effect of oridonin on d-galactosamine (d-GalN)/lipopolysaccharide (LPS)-induced ALI and whether the effect is mediated by NLRP3. Mice were pretreated with oridonin (5 or 10 mg/kg) for 3 days. Then, they were injected with d-GalN (400 mg/kg) and LPS (40 µg/kg). The levels of inflammatory factors were measured by RT-PCR, Western blot, and enzyme-linked immunosorbent assay. We confirmed that oridonin significantly alleviated ALI induced by d-GalN/LPS in mice. Oridonin markedly decreased the inflammatory response by reducing the levels of inflammatory cytokines. More importantly, oridonin markedly reduced the expression of NLRP3, caspase-1, IL-18, and IL-1ß. This study showed that oridonin has a protective effect on d-GalN/LPS-induced ALI, and the underlying mechanisms may be associated with the inhibition of the NLRP3 inflammatory pathways.

Metabolism and Toxicity of Emodin: Genome-Wide Association Studies Reveal Hepatocyte Nuclear Factor 4α Regulates UGT2B7 and Emodin Glucuronidation.

Emodin is the main toxic component in Chinese medicinal herbs such as rhubarb. Our previous studies demonstrated that genetic polymorphisms of UDP-glucuronosyltransferase 2B7 (UGT2B7) had an effect on the glucuronidation and detoxification of emodin. This study aimed to reveal the transcriptional regulation mechanism of UGT2B7 on emodin glucuronidation and its effect on toxicity. Emodin glucuronic activity and genome and transcriptome data were obtained from 36 clinical human kidney tissues. The genome-wide association studies (GWAS) identified that four single nucleotide polymorphisms (SNPs) (rs6093966, rs2868094, rs2071197, and rs6073433), which were located on the hepatocyte nuclear factor 4α (HNF4A) gene, were significantly associated with the emodin glucuronidation (p < 0.05). Notably, rs2071197 was significantly associated with the gene expression of HNF4A and UGT2B7 and the glucuronidation of emodin. The gene expression of HNF4A showed a high correlation with UGT2B7 (R2 = 0.721, p = 5.83 × 10-11). The luciferase activity was increased 7.68-fold in 293T cells and 2.03-fold in HepG2 cells, confirming a significant transcriptional activation of UGT2B7 promoter by HNF4A. The knockdown of HNF4A in HepG2 cells (36.6%) led to a significant decrease of UGT2B7 (19.8%) and higher cytotoxicity (p < 0.05). The overexpression of HNF4A in HepG2 cells (31.2%) led to a significant increase of UGT2B7 (24.4%) and improved cell viability (p < 0.05). Besides, HNF4A and UGT2B7 were both decreased in HepG2 cells and rats after treatment with emodin. In conclusion, emodin used long term or in high doses could inhibit the expression of HNF4A, thereby reducing the expression of UGT2B7 and causing hepatotoxicity.

Emodin-induced hepatotoxicity was exacerbated by probenecid through inhibiting UGTs and MRP2.

Aggravating effect of probenecid (a traditional anti-gout agent) on emodin-induced hepatotoxicity was evaluated in this study. 33.3% rats died in combination group, while no death was observed in rats treated with emodin alone or probenecid alone, indicating that emodin-induced (150 mg/kg) hepatotoxicity was exacerbated by probenecid (100 mg/kg). In toxicokinetics-toxicodynamics (TK-TD) study, aspartate aminotransferase (AST) and systemic exposure (area under the serum concentration-time curve, AUC) of emodin and its glucuronide were significantly increased in rats after co-administrated with emodin and probenecid for 28 consecutive days. Results showed that the increased AUC (increased by 85.9%) of emodin was mainly caused by the decreased enzyme activity of UDP-glucuronosyltransferases (UGTs, decreased by 11.8%-58.1%). In addition, AUC of emodin glucuronide was increased 5-fold, which was attributed to the decrease of multidrug-resistant-protein 2 (MRP2) protein levels (decreased by 54.4%). Similarly, in vitro experiments proved that probenecid reduced the cell viability of emodin-treated HepG2 cells through inhibiting UGT1A9, UGT2B7 and MRP2. Our findings demonstrated that emodin-induced hepatoxicity was exacerbated by probenecid through inhibition of UGTs and MRP2 in vivo and in vitro, indicating that gout patients should avoid taking emodin-containing preparations in combination with probenecid for a long time.

The efficacy and safety of hydroxychloroquine at different doses and courses for COVID-19 prevention: a systematic review and network meta-analysis.

BACKGROUND: The optimal strategy for using hydroxychloroquine to prevent coronavirus disease 2019 (COVID-19) in patients, either before or after exposure, remains unclear. We evaluated the safety and efficacy of different doses and treatment durations of hydroxychloroquine for COVID-19 prevention. METHOD: Databases including PubMed, Web of Science, Cochrane Library, EMBASE, Medline, and ClinicalTrials.gov were systematically searched for randomized controlled trials (RCTs) comparing different doses of hydroxychloroquine for COVID-19 prevention, from their inception to February 2024. RESULTS: A total of 20 RCTs involving 12,372 patients were included. Meta-analysis results showed no significant difference between the hydroxychloroquine and control groups in reducing the incidence of syndrome coronavirus type 2 (SARS-CoV-2) positivity (OR = 0.83, 95% CI = 0.67, 1.03). However, the subgroup receiving a daily dose of 200-400 mg (OR = 0.62, 95% CI = 0.51, 0.75) and a treatment duration of 5-8 weeks (OR = 0.52, 95% CI = 0.31, 0.88) showed statistically significant reductions in SARS-CoV-2 positivity. According to the surface under the cumulative ranking curve (SUCRA), the most effective intervention was a 200-400 mg dose for 5-8 weeks. . CONCLUSIONS: A hydroxychloroquine dose of 200-400 mg for a duration of 5-8 weeks may moderately reduce the risk of COVID-19 with a relatively low risk of adverse events.

Restoration of lipid homeostasis between TG and PE by the LXRα-ATGL/EPT1 axis ameliorates hepatosteatosis.

Converting lipid disturbances in response to energy oversupply into healthy lipid homeostasis is a promising therapy to alleviate hepatosteatosis. Our clinical studies found that a further elevation of triglyceride (TG) in obese patients with the body mass index (BMI) greater than 28 was accompanied by a further reduction of phosphatidylethanolamine (PE). Shorter survival and poor prognosis were shown for the patients with high TG and low PE levels. Liver X receptor alpha (LXRα) knockout mice aggravated high-fat diet (HFD)-induced obesity and lipid disorders, making the TG enrichment and the PE decrease more pronounced according to the liver lipidomics analysis. The RNA-seq from mice liver exhibited that these metabolism disorders were attributed to the decline of Atgl (encoding the TG metabolism enzyme ATGL) and Ept1 (encoding the PE synthesis enzyme EPT1) expression. Mechanistic studies uncovered that LXRα activated the ATGL and EPT1 gene via direct binding to a LXR response element (LXRE) in the promoter. Moreover, both the supplement of PE in statin or fibrate therapy, and the LXRα inducer (oridonin) ameliorated cellular lipid deposition and lipotoxicity. Altogether, restoration of lipid homeostasis of TG and PE via the LXRα-ATGL/EPT1 axis may be a potential approach for the management of hepatosteatosis and metabolic syndrome.

Artificial intelligence-driven electrochemical immunosensing biochips in multi-component detection.

Electrochemical Immunosensing (EI) combines electrochemical analysis and immunology principles and is characterized by its simplicity, rapid detection, high sensitivity, and specificity. EI has become an important approach in various fields, such as clinical diagnosis, disease prevention and treatment, environmental monitoring, and food safety. However, EI multi-component detection still faces two major bottlenecks: first, the lack of cost-effective and portable detection platforms; second, the difficulty in eliminating batch differences and accurately decoupling signals from multiple analytes. With the gradual maturation of biochip technology, high-throughput analysis and portable detection utilizing the advantages of miniaturized chips, high sensitivity, and low cost have become possible. Meanwhile, Artificial Intelligence (AI) enables accurate decoupling of signals and enhances the sensitivity and specificity of multi-component detection. We believe that by evaluating and analyzing the characteristics, benefits, and linkages of EI, biochip, and AI technologies, we may considerably accelerate the development of EI multi-component detection. Therefore, we propose three specific prospects: first, AI can enhance and optimize the performance of the EI biochips, addressing the issue of multi-component detection for portable platforms. Second, the AI-enhanced EI biochips can be widely applied in home care, medical healthcare, and other areas. Third, the cross-fusion and innovation of EI, biochip, and AI technologies will effectively solve key bottlenecks in biochip detection, promoting interdisciplinary development. However, challenges may arise from AI algorithms that are difficult to explain and limited data access. Nevertheless, we believe that with technological advances and further research, there will be more methods and technologies to overcome these challenges.

Oridonin restores hepatic lipid homeostasis in an LXRα-ATGL/EPT1 axis-dependent manner.

Hepatosteatosis is characterized by abnormal accumulation of triglycerides (TG), leading to prolonged and chronic inflammatory infiltration. To date, there is still a lack of effective and economical therapies for hepatosteatosis. Oridonin (ORI) is a major bioactive component extracted from the traditional Chinese medicinal herb Rabdosia rubescens. In this paper, we showed that ORI exerted significant protective effects against hepatic steatosis, inflammation and fibrosis, which was dependent on LXRα signaling. It is reported that LXRα regulated lipid homeostasis between triglyceride (TG) and phosphatidylethanolamine (PE) by promoting ATGL and EPT1 expression. Therefore, we implemented the lipidomic strategy and luciferase reporter assay to verify that ORI contributed to the homeostasis of lipids via the regulation of the ATGL gene associated with TG hydrolysis and the EPT1 gene related to PE synthesis in a LXRα-dependent manner, and the results showed the TG reduction and PE elevation. In detail, hepatic TG overload and lipotoxicity were reversed after ORI treatment by modulating the ATGL and EPT1 genes, respectively. Taken together, the data provide mechanistic insights to explain the bioactivity of ORI in attenuating TG accumulation and cytotoxicity and introduce exciting opportunities for developing novel natural activators of the LXRα-ATGL/EPT1 axis for pharmacologically treating hepatosteatosis and metabolic disorders.

A Review of Electrochemical Sensors for the Detection of Glycated Hemoglobin.

Glycated hemoglobin (HbA1c) is the gold standard for measuring glucose levels in the diagnosis of diabetes due to the excellent stability and reliability of this biomarker. HbA1c is a stable glycated protein formed by the reaction of glucose with hemoglobin (Hb) in red blood cells, which reflects average glucose levels over a period of two to three months without suffering from the disturbance of the outside environment. A number of simple, high-efficiency, and sensitive electrochemical sensors have been developed for the detection of HbA1c. This review aims to highlight current methods and trends in electrochemistry for HbA1c monitoring. The target analytes of electrochemical HbA1c sensors are usually HbA1c or fructosyl valine/fructosyl valine histidine (FV/FVH, the hydrolyzed product of HbA1c). When HbA1c is the target analyte, a sensor works to selectively bind to specific HbA1c regions and then determines the concentration of HbA1c through the quantitative transformation of weak electrical signals such as current, potential, and impedance. When FV/FVH is the target analyte, a sensor is used to indirectly determine HbA1c by detecting FV/FVH when it is hydrolyzed by fructosyl amino acid oxidase (FAO), fructosyl peptide oxidase (FPOX), or a molecularly imprinted catalyst (MIC). Then, a current proportional to the concentration of HbA1c can be produced. In this paper, we review a variety of representative electrochemical HbA1c sensors developed in recent years and elaborate on their operational principles, performance, and promising future clinical applications.

Effect of oridonin on oxylipins in the livers of mice with acute liver injury induced by D-galactosamine and lipopolysaccharide.

BACKGROUND AND PURPOSE: Oridonin (Ori) has been shown to protect against acute liver injury (ALI) induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS). Oxylipins are oxidation products of polyunsaturated fatty acids (PUFAs) and are key proinflammatory mediators. This study aimed to investigate the changes in oxylipins in the livers of mice with D-GalN/LPS-induced ALI and the effects of Ori on these changes. RESULTS: 54 oxylipins in liver tissues were identified and qualitatively and quantitatively analyzed by ultra-performance liquid chromatography-electrospray ionization triple quadrupole mass spectrometry (UPLC-QTRAP/MS/MS). The levels of 12-HETE, 12-HEPE, 14(S)-HDHA, PGE2, dihomo-γ-linolenic acid and 13-HOTrE in the liver were significantly increased in the D-GalN/LPS-induced ALI group compared with the control group, and the levels of EPA and 7-HDHA were significantly decreased. However, pretreatment with Ori dramatically decreased the levels of 12-HETE, 12-HEPE, 14(S)-HDHA, PGE2 and 13-HOTrE compared with those of the ALI group and induced 7-HDHA and 15-oxoETE. Moreover, Ori reduced the protein levels of COX-1, COX-2, ALOX5, ALOX12 and ALOX15 induced by D-GalN/LPS, indicating that Ori altered oxylipins through the COX and LOX pathways. CONCLUSIONS: These results suggest that the protective effect of Ori on ALI is partly mediated by affecting the oxylipin pathway.

Measurement methods of single cell drug response.

In the last decades, a wide multitude of research activity has been focused on the development of new drugs, and devoted to overcome the challenges of high cost and low efficiency in drug evaluation. The measurement of drug response at the single cell level is a quicker, more direct and more accurate way to reflect drug efficacy, which can shorten the drug development period and reduce research costs. Therefore, the single cell drug response (SCDR) measurement technology has aroused extensive attention from researchers, and has become a hot topic in the fields of drug research and cell biology. Recent years have seen the emergence of various SCDR measurement technologies that feature different working principles and different levels of measurement performance. To better examine, compare and summarize the characteristics and functions of these technologies, we select signal-to-noise ratio, throughput, content, invasion, and device complexity as the criteria to evaluate them from the drug efficacy perspective. This review aims to highlight sixteen kinds of SCDR measurement technologies, including patch-clamp technique, live-cell interferometry, capillary electrophoresis, secondary ion mass spectrometry, and more, and report widespread representative examples of SCDR measurement the recent approaches for over the past forty years. Based on their reaction principles, these technologies are classified into four categories: electrical, optical, electrochemical, and mass spectrometry, and a detailed comparison is made between them. After in-depth understanding of these technologies, it is expected to improve or integrate these technologies to propose better SCDR measurement strategies, and explore methods in new drug development and screening, as well as disease diagnosis and treatment.

Glycated Hemoglobin Electrochemical Immunosensor Based on Screen-Printed Electrode.

An electrochemical HbA1c sensor with high sensitivity and good specificity is proposed based on the electrochemical immune principle. The reproducibility and conductivity of the electrode are improved by depositing gold nanoparticles (AuNPs) on the surface of the screen-printed electrode (SPE). The HbA1c antibodies are immobilized on the surface of the modified electrode by adsorption to capture the HbA1c in the sample. The hindering effect of HbA1c on the electrode transfer reaction was exploited as the HbA1c detection mechanism. The electrode's properties were characterized by electrochemical impedance spectroscopy (EIS), and the measurement properties of the electrode were analyzed using differential pulse voltammetry (DPV) and cyclic voltammetry (CV). The experimental results show that the peak current signal of the electrochemical immunosensor produced a linear response to HbA1c in the concentration range of 20-200 µg/mL, a linear relationship coefficient of 0.9812, a detection limit of 15.5 µg/mL, and a sensitivity of 0.0938 µA/µg·mL-1. The sensor delivered satisfactory repeatability, stability, and anti-interference performance. Due to its small size, high sensitivity, and wide linear detection range, it is expected to play a significant role in managing diabetes at home.

A highly selective and sensitive chemiluminescent probe for leucine aminopeptidase detection in vitro, in vivo and in human liver cancer tissue.

Leucine aminopeptidase (LAP) is involved in tumor cell proliferation, invasion, and angiogenesis, and is a well-known tumor marker. In recent years, chemiluminescence has been widely used in the field of biological imaging, due to it resulting in a high sensitivity and excellent signal-to-noise ratio. Here, we report the design, synthesis, and evaluation of the first LAP-activated chemiluminescent probe for LAP detection and imaging. The probe initially had no chemiluminescence but produced an extremely strong chemiluminescence after the release of the dioxetane intermediate in the presence of LAP. The probe had high selectivity over other proteases and higher signal-to-noise ratios than commercial fluorophores. Real-time imaging results indicated that the chemiluminescence was remarkably enhanced at the mice tumor site after the probe was injected. Furthermore, the chemiluminescence of this probe in the cancerous tissues of patients was obviously improved compared to that of normal tissues. Taken together, this study has developed the first LAP-activable chemiluminescent probe, which could be potentially used in protein detection, disease diagnosis, and drug development.

LXR-Mediated Regulation of Marine-Derived Piericidins Aggravates High-Cholesterol Diet-Induced Cholesterol Metabolism Disorder in Mice.

Reported as two antirenal cell carcinoma (RCC) drug candidates, marine-derived compounds piericidin A (PA) and glucopiericidin A (GPA) exhibit hepatotoxicity in renal carcinoma xenograft mice. Proteomics and transcriptomics reveal the hepatotoxicity related with cholesterol disposition since RCC is characterized by cholesterol accumulation. PA/GPA aggravate hepatotoxicity in high-cholesterol diet (HCD)-fed mice while exhibiting no toxicity in chow diet-fed mice. High cholesterol accumulation in liver is liver X receptor (LXR)-mediated cytochrome P450 family 7 subfamily a member 1 (CYP7A1) depression and low-density lipoprotein receptor (LDLR) activation. The farnesoid X nuclear receptor (FXR) is also depressed with a downregulated target gene OSTα. Different from PA directly combined with LXRα as an inhibitor, GPA exists as a prodrug in the liver and exerts toxic effects due to transformation into PA. Surface plasmon resonance (SPR) and docking results of 17 piericidins illustrate that glycosides exert no LXRα binding activity. A longer survival time of GPA-treated mice indicates that further exploration in anti-RCC drug research should focus on reducing glycosides transformed into PA and concentrating in the kidney tumor rather than the liver for lowering the risk of hepatotoxicity.

AI powered electrochemical multi-component detection of insulin and glucose in serum.

Multi-component detection of insulin and glucose in serum is of great importance and urgently needed in clinical diagnosis and treatment due to its economy and practicability. However, insulin and glucose can hardly be determined by traditional electrochemical detection methods. Their mixed oxidation currents and rare involvement in the reaction process make it difficult to decouple them. In this study, AI algorithms are introduced to power the electrochemical method to conquer this problem. First, the current curves of insulin, glucose, and their mixed solution are obtained using cyclic voltammetry. Then, seven features of the cyclic voltammetry curve are extracted as characteristic values for detecting the concentrations of insulin and glucose. Finally, after training using machine learning algorithms, insulin and glucose concentrations are decoupled and regressed accurately. The entire detection process only takes three minutes. It can detect insulin at the pmol level and glucose at the mmol level, which meets the basic clinical requirements. The average relative error in predicting insulin concentrations is around 6.515%, and that in predicting glucose concentrations is around 4.36%. To verify the performance and effectiveness of the proposed method, it is used to determine the concentrations of insulin and glucose in fetal bovine serum and real clinical serum samples. The results are satisfactory, demonstrating that the method can meet basic clinical needs. This multi-component testing system delivers acceptable detect limit and accuracy and has the merits of low cost and high efficiency, holding great potential for use in clinical diagnosis.

Regulation of cytochrome P450 4F11 expression by liver X receptor alpha.

Cytochrome P450 4F (CYP4F) enzymes are responsible for the metabolism of eicosanoids, which play important roles in inflammation. Nuclear receptor liver X receptor alpha (LXRα) is a critical signal node connecting inflammation and lipid metabolism. Studies revealed that the release of cytokines and nuclear factor-κB (NF-κB) can change the CYP4F11 expression in HepG2 cells. However, the effect of LXRα on the CYP4F family and the underlying mechanism remain unclear. This study found that CYP4F11 is a target gene of LXRα. Luciferase assays and siRNA transfection showed that LXRα increased the transcription of CYP4F11 and LXRα agonist GW3965 could induce the expression of CYP4F11 by activating the LXRα-CYP4F11 pathway. Besides, overexpression of CYP4F11 could decrease TNF-α and IL-1ß in lipopolysaccharide (LPS)-induced THP-1 cells. The finding of the regulation of CYP4F11 may contribute to the anti-inflammatory activity of LXRα agonists.

Microliter Sample Insulin Detection Using a Screen-Printed Electrode Modified by Nickel Hydroxide.

The monitoring of insulin, which is the only hormone that helps regulate blood glucose levels in the body, plays a key role in the diagnosis and treatment of diabetes. However, most techniques today involve complicated electrode fabrication and testing processes, which are time-consuming and costly, and require a relatively large volume of sample. To overcome these drawbacks, we present here a low-cost insulin detection method based on a screen-printed electrode (SPE) modified by nickel hydroxide (Ni(OH)2). This novel method only requires 300 µL of insulin sample, and the time it takes for electrode preparation is about 12 times shorter than traditional electrode fabrication methods such as coating and sol-gel methods. The electrochemical behaviors of the Ni(OH)2-coated SPE (NSPE) sensing area in insulin aqueous solutions are studied using cyclic voltammetry, amperometric i-t curves, and electrochemical impedance spectroscopy. The results demonstrate that the NSPE sensing surface has excellent detection properties, such as a high sensitivity of 15.3 µA·µM-1 and a low detection limit of 138 nM. It takes a short time (∼10 min) to prepare the NSPE sensing surface, and only two drops (∼300 µL) of insulin samples are required in the detection process. Moreover, the selectivity of this method for insulin detection is verified by detecting mixtures of insulin and ascorbic acid or bovine hemoglobin. Finally, we discuss the potential clinical applications of this method by detecting various concentrations of insulin in human serum.

3D Printed Multi-Functional Hydrogel Microneedles Based on High-Precision Digital Light Processing.

Traditional injection and extraction devices often appear painful and cumbersome for patients. In recent years, polymer microneedles (MNs) have become a novel tool in the field of clinical medicine and health. However, the cost of building MNs into any shapes still remains a challenge. In this paper, we proposed hydrogel microneedles fabricated by high-precision digital light processing (H-P DLP) 3D printing system. Benefits from the sharp protuberance and micro-porous of the hydrogel microneedle, the microneedle performed multifunctional tasks such as drug delivery and detection with minimally invasion. Critical parameters for the fabrication process were analyzed, and the mechanical properties of MNs were measured to find a balance between precision and stiffness. Results shows that the stiffness and precision were significantly influenced by exposure time of each layer, and optimized printing parameters provided a balance between precision and stiffness. Bio-compatible MNs based on our H-P DLP system was able to execute drug injection and drug detection in our experiments. This work provided a low-cost and fast method to build MNs with 3D building, qualified the mechanical performance, drug injection, drug detection ability of MNs, and may be helpful for the potential clinical application.

Exploring the Natural Piericidins as Anti-Renal Cell Carcinoma Agents Targeting Peroxiredoxin 1.

Anti-renal cell carcinoma (RCC) agents with new mechanisms of action are urgently needed. Twenty-seven natural products of the piericidin class, including 17 new ones, are obtained from a marine-derived Streptomyces strain, and several of them show strong inhibitory activities against ACHN renal carcinoma cells. By exploring the mechanisms of two representative natural piericidin compounds, piericidin A (PA) and glucopiericidin A (GPA), peroxiredoxin 1 (PRDX1) is detected as a potential target by transcriptome data of PA-treated ACHN cells, as well as the paired RCC tumor versus adjacent nontumor tissues. PA and GPA induce cell apoptosis through reducing the reactive oxygen species level caused by upregulated PRDX1 mRNA and protein level subsequently and exhibit potent antitumor efficacy in nude mice bearing ACHN xenografts, with increasing PRDX1 expression in tumor. The interaction between PA/GPA and PRDX1 was supported by the docking analysis and surface plasmon resonance. Moreover, the translocation of PRDX1 into the nucleus forced by PA/GPA is proposed to be a key factor for the anti-RCC procedure. Piericidins provide a novel scaffold for further development of potent anti-RCC agents, and the new action mechanism of these agents targeting PRDX1 may improve upon the limitations of existing targeted drugs for the treatment of renal cancer.