Direct 3D printing of triple-responsive nanocomposite hydrogel microneedles for controllable drug delivery.

Hydrogel microneedle patches have emerged as promising platforms for painless, minimally invasive, safe, and portable transdermal drug administration. However, the conventional mold-based fabrication processes and inherent single-functionality of such microneedles present significant hurdles to broader implementation. Herein, we have developed a novel approach utilizing a precursor solution of robust nanocomposite hydrogels to formulate photo-printable inks suitable for the direct 3D printing of high-precision, triple-responsive hydrogel microneedle patches through digital light processing (DLP) technology. The ink formulation comprises four functionally diverse monomers including 2-(dimethylamino)ethyl methacrylate, N-isopropylacrylamide, acrylic acid, and acrylamide, which were crosslinked by aluminum hydroxide nanoparticles (AH NPs) acting as both reinforcing agents and crosslinking centers. This results in the formation of a nanocomposite hydrogel characterized by exceptional mechanical strength, an essential attribute for the 3D printing of hydrogel microneeedle patches. Furthermore, this innovative 3D printing strategy facilitates facile customization of microneedle geometry and patch dimensions. As a proof-of-concept, we employed the fabricated hydrogel microneedles for transdermal delivery of bovine serum albumin (BSA). Importantly, these hydrogel microneedles displayed no cytotoxic effects and exhibited triple sensitivity to pH, temperature and glucose levels, thereby enabling more precise on-demand drug delivery. This study provides a universal method for the rapid fabrication of hydrogel microneedles with smart responsiveness for transdermal drug delivery applications.

Development and validation of a novel nomogram for predicting overall survival patients with neuroblastoma.

PURPOSE: The aim of this study was to develop a nomogram specially for predicting overall survival (OS) for Chinese patients with neuroblastoma (NB). METHODS: Patients with pathologically confirmed NB who were newly diagnosed and received treatments at our hospital from October 2013 to October 2021 were retrospectively reviewed. The nomogram for OS were built based on Cox regression analysis. The validation of the prognostic model was evaluated by concordance index (C-index), calibration curves, and decision curve analyses (DCAs). RESULTS: A total of 254 patients with NB were included in this study. They were randomly divided into a training cohort (n = 178) and a validation cohort (n = 76) at a ratio of 7:3. Multivariate analyses revealed that prognostic variables significantly related to the OS were age at diagnosis, bone metastasis, hepatic metastasis, INSS stage, MYCN status and DNA ploidy. The nomogram was constructed based on above 6 factors. The C-index values of the nomogram for predicting 3-year and 5-year OS were 0.926 and 0.964, respectively. The calibration curves of the nomogram showed good consistency between nomogram prediction and actual survival. The DCAs showed great clinical usefulness of the nomograms. Furthermore, patients with low-risk identified by our nomogram had much higher OS than those with high-risk (p < 0.001). CONCLUSION: The nomogram we constructed exhibited good predictive performance and could be used to assist clinicians in their decision-making process.

Landscape of m6A RNA methylation regulators in liver cancer and its therapeutic implications.

Liver cancer remains as the third leading cause of cancer-related death globally as of 2020. Despite the significant progress made in the field of liver cancer treatment, there is still a lack of effective therapies in patients with advanced cancer and the molecular mechanisms underlying liver cancer progression remain largely elusive. N6-methyladenosine (m6A) modification, as the most prevalent and abundant internal RNA modification in eukaryotic RNAs, plays an essential role in regulating RNA metabolism including RNA splicing, stability, translation, degradation. To date, there is mounting evidence showing that m6A dysregulation is closely associated with the onset and development of many tumors including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and hepatoblastoma (HB). In this review, we summarize the last research progress regarding the functions of m6A-related regulators in liver cancer and its underlying mechanisms. Additionally, we also discuss the therapeutic applications of m6A-based inhibitors in liver cancer treatment.

Multi-material 3D printed eutectogel microneedle patches integrated with fast customization and tunable drug delivery.

Microneedle patches are emerging multifunctional platforms for transdermal diagnostics and drug delivery. However, it still remains challenging to develop smart microneedles integrated with customization, sensing, detection and drug delivery by 3D printing strategy. Here, we present an innovative but facile strategy to rationally design and fabricate multifunctional eutectogel microneedle (EMN) patches via multi-material 3D printing. Polymerizable deep eutectic solvents (PDES) were selected as printing inks for rapid one-step fabrication of 3D printing functional EMN patches due to fast photopolymerization rate and ultrahigh drug solubility. Moreover, stretchable EMN patches incorporating rigid needles and flexible backing layers were easily realized by changing PDES compositions of multi-material 3D printing. Meanwhile, we developed multifunctional smart multi-material EMN patches capable of performing wireless monitoring of body movements, painless colorimetric glucose detection, and controlled transdermal drug delivery. Thus, such multi-material EMN system could provide an effective platform for the painless diagnosis, detection, and therapy of a variety of diseases.

Transparent, Mechanically Robust, Adhesive, Temperature-Tolerant, and 3D Printable Nanocomposite Ionogels for Flexible Sensors.

Ionogels are emerging as soft materials for flexible strain sensors. However, the integration of multiple functionalities into a single ionogel for diverse applications in complex scenarios remains a challenge. In this study, we present a multifunctional nanocomposite ionogel that combines high strength, transparency, stretchability, temperature tolerance, adhesiveness, and 3D printing capabilities. The ionogels are fabricated through a one-step photopolymerization process involving acrylic acid and 2-acrylamide-2-methylpropanesulfonic acid in an ionic liquid, with Al(OH)3 nanoparticles serving as cross-linkers. The resulting ionogels exhibit robust noncovalent interactions, including ionic coordination, hydrogen bonding, and ionic dipole interactions, providing exceptional mechanical strength, conductivity, and wide temperature tolerance while ensuring strong adhesion to various substrates. Wearable strain sensors based on these ionogels can accurately detect and differentiate a range of movements, from large body motions such as bending limbs to subtle distinctions such as writing different letters. Additionally, the pregel solution can serve as printing ink for the rapid and efficient mass production of 3D printed high-precision microcircuits. Impressively, the nanocomposite ionogels exhibit a high latent heat value of 240 J g-1 at a melting temperature of -65 °C, suggesting significant potential for cold energy storage in ultralow-temperature cold-chain transportation systems. Thus, these outstanding features of the ionogels offer a promising strategy for advancing wearable electronics and cold energy storage systems.

Targeted modulation of gut microbiota by traditional Chinese medicine and natural products for liver disease therapy.

The gut microbiota not only constitutes intestinal microenvironment homeostasis and human health but also exerts indispensable roles in the occurrence and progression of multiple liver diseases, including alcohol-related liver disease, nonalcoholic fatty liver disease, autoimmune liver disease and liver cancer. Given the therapeutic status of these diseases, their prevention and early therapy are crucial, and the detailed mechanism of gut microbiota in liver disease urgently needs to be explored. Meanwhile, multiple studies have shown that various traditional Chinese medicines, such as Si Miao Formula, Jiangzhi Granules, Liushen Capsules, Chaihu-Shugan Power, Cassiae Semen and Gynostemma, as well as some natural products, including Costunolide, Coprinus comatus polysaccharide, Antarctic krill oil, Oridonin and Berberine, can repair liver injury, improve fatty liver, regulate liver immunity, and even inhibit liver cancer through multiple targets, links, and pathways. Intriguingly, the aforementioned effects demonstrated by these traditional Chinese medicines and natural products have been shown to be closely related to the gut microbiota, directly driving the strategy of traditional Chinese medicines and natural products to regulate the gut microbiota as one of the breakthroughs in the treatment of liver diseases. Based on this, this review comprehensively summarizes and discusses the characteristics, functions and potential mechanisms of these medicines targeting gut microbiota during liver disease treatment. Research on the potential effects on gut microbiota and the regulatory mechanisms of traditional Chinese medicine and natural products provides novel insights and significant references for developing liver disease treatment strategies. In parallel, such explorations will enhance the comprehension of traditional Chinese medicine and natural products modulating gut microbiota during disease treatment, thus facilitating their clinical investigation and application.

Epigenetics and genetics of hepatoblastoma: Linkage and treatment.

Hepatoblastoma is a malignant embryonal tumor with multiple differentiation modes and is the clearest liver malignancy in children. However, little is known about genetic and epigenetic events in Hepatoblastoma. Increased research has recently demonstrated, unique genetic and epigenetic events in Hepatoblastoma, providing insights into its origin and precise treatment. Some genetic disorders and congenital factors are associated with the risk of Hepatoblastoma development, such as the Beckwith-Wiedemann syndrome, Familial Adenomatous polyposis, and Hemihypertrophy. Epigenetic modifications such as DNA modifications, histone modifications, and non-coding RNA regulation are also essential in the development of Hepatoblastoma. Herein, we reviewed genetic and epigenetic events in Hepatoblastoma, focusing on the relationship between these events and cancer susceptibility, tumor growth, and prognosis. By deciphering the genetic and epigenetic associations in Hepatoblastoma, tumor pathogenesis can be clarified, and guide the development of new anti-cancer drugs and prevention strategies.

Advances in RNA Epigenetic Modifications in Hepatocellular Carcinoma and Potential Targeted Intervention Strategies.

The current interventions for hepatocellular carcinoma (HCC) are not satisfactory, and more precise targets and promising strategies need to be explored. Recent research has demonstrated the non-negligible roles of RNA epigenetic modifications such as N6-methyladenosine (m6A) and 5-methylcytosine (m5C) in various cancers, including HCC. However, the specific targeting mechanisms are not well elucidated. In this review, we focus on the occurrence and detailed physiopathological roles of multiple RNA modifications on diverse RNAs closely related to the HCC process. In particular, we highlight fresh insights into the impact mechanisms of these posttranscriptional modifications on the whole progression of HCC. Furthermore, we analyzed the possibilities and significance of these modifications and regulators as potential therapeutic targets in HCC treatment, which provides the foundation for exploring targeted intervention strategies. This review will propel the identification of promising therapeutic targets and novel strategies that can be translated into clinical applications for HCC treatment.

Assessment of continuous neutrophil CD64 index measurement for diagnosing sepsis and predicting outcome in a Chinese pediatric intensive care unit: a prospective study.

BACKGROUND: The high affinity immunoglobulin-Fc fragment receptor I CD64 on neutrophils is widely assumed to be a useful biomarker in the early identification of sepsis, and it improves outcomes. We aimed to determine its ability to diagnose sepsis and predict its prognosis with continuous measurements. METHODS: A total of 335 patients admitted to a Chinese PICU were prospectively stratified into two groups according to the presence of sepsis (defined by clinical criteria for sepsis) between 2018 and 2019. Serum concentrations of the nCD64 index, C-reactive protein (CRP), and procalcitonin (PCT) were measured. Sensitivity, specificity and receiver operating characteristic (ROC) curves were calculated to evaluate the diagnostic value for sepsis. A multiple logistic regression model was used to estimate the prognostic value of continuous nCD64 index measurement for in-hospital death. RESULTS: The baseline nCD64 index and levels of PCT and CRP were significantly higher in septic children than in nonseptic children (P<0.05). The nCD64 index presented a higher sensitivity (0.90), specificity (0.78) and area under the ROC curve [0.91 (0.90, 0.93)] than CRP and PCT in discriminating septic children with an optimal cutoff value of 5.78. The nCD64 index decreased with the progression of sepsis, and the baseline nCD64 index was strongly associated with in-hospital death (OR: 2.18, 95% CI: 1.02-4.74). Moreover, the more rapidly the nCD64 index declined, the lower the in-hospital death rate was (OR: 0.89, 95% CI: 0.63-1.35) after adjusting for the baseline nCD64 index and other confounders. CONCLUSIONS: The nCD64 index was not only effective for the early diagnosis of childhood sepsis but also positively associated with the prognosis of sepsis. Moreover, the nCD64 decline was inversely associated with the in-hospital death rate.

Total saponin of Dioscorea collettii attenuates MSU crystal­induced inflammation via inhibiting the activation of the NALP3 inflammasome and caspase­1 in THP­1 macrophages.

Total saponins extracted from Dioscorea collettii (TSD), extracts of the Chinese herb Dioscorea, are thought to exhibit therapeutic benefit in gouty arthritis. However, its exact mechanism remains unclear. The current study aimed to elucidate the underlying mechanisms by investigating the effects of TSD on the inflammation induced by monosodium urate (MSU) crystals in THP­1 macrophages. The viability of THP­1 macrophages was examined using the MTT assay and the levels of inflammatory cytokines, including interleukin (IL)­1ß, IL­18 and tumor necrosis factor (TNF)­α, released by the cells were quantitatively measured using ELISA kits. The results revealed that the protein level of cluster of differentiation 11b increased in THP­1 cells treated with 100 ng/ml phorbol ester, suggesting that monocytic THP­1 cells were successfully differentiated into macrophages. TSD decreased the levels of inflammatory cytokines, including TNF­α, IL­18 and IL­1ß, secreted by THP­1 macrophages. As the release of IL­1ß and IL­18 is dependent on the NLR family pyrin domain containing 3 (NALP3) inflammasome and caspase­1, the current study investigated the effect of TSD on the aforementioned proteins. The results revealed that TSD decreased the protein levels of NALP3 and apoptosis­associated speck­like, which serve important roles in the assembly of the NALP3 inflammasome. Furthermore, NALP3 inflammasome­related proteins were also decreased by TSD in rotenone induced THP­1 macrophages, TSD inhibited the activation of caspase­1 and rotenone­induced NALP3 inflammasome activation in THP­1 macrophages. The results obtained in the current study revealed that TSD attenuated MSU crystal­induced inflammation by inhibiting rotenone­induced activation of the NALP3 inflammasome and caspase­1, suggesting that these two proteins may be novel targets for the treatment of gouty arthritis.

Diagnostic accuracy of procalcitonin for overall and complicated acute appendicitis in children: a meta-analysis.

BACKGROUND: Diagnostic value of procalcitonin (PCT) for acute appendicitis (AA) has been evaluated in adult patients, but the application in children remains controversial. The aim of this study was to evaluate the diagnostic value of PCT for overall and complicated AA in children. METHODS: The PubMed, EMBASE, Web of Science, Cochrane Database of Systematic Reviews, Chinese National Knowledge Infrastructure, and Wanfang were searched along with reference lists of relevant articles up to January 2018 without language restrictions. Original articles that reported the performance of PCT in the diagnosis of pediatric AA and associated complications were selected. To assess the diagnostic value of PCT, sensitivity, specificity, diagnostic odds ratios (DORs), summary receiver operating characteristic (ROC) curves, area under the curve (AUC), and 95% confidence intervals (95% CIs) were estimated. RESULTS: Seven qualifying studies (504 confirmed AA and 368 controls) from 6 countries for overall AA and 4 studies (187 complicated AA and 185 uncomplicated AA) for complicated AA from 3 countries were identified. The pooled sensitivity and specificity of PCT for the diagnosis of pediatric AA were 0.62 (95% CI: 0.57-0.66) and 0.86 (95% CI: 0.82-0.89), respectively. The DOR was 21.4 (95% CI: 3.64-126.1) and the AUC was 0.955. PCT was more accurate in diagnosing complicated appendicitis, with a pooled sensitivity of 0.89 (95% CI: 0.84-0.93), specificity of 0.90 (95% CI: 0.86-0.94), and DOR of 76.73 (95% CI: 21.6-272.9). CONCLUSION: This meta-analysis showed that PCT may have potential value in diagnosing pediatric AA. Moreover, PCT had greater diagnostic value in identifying pediatric complicated appendicitis.

Saponins extracted from Dioscorea collettii rhizomes regulate the expression of urate transporters in chronic hyperuricemia rats.

OBJECTIVE: The current study aimed to investigate whether the saponins, bioactive component of effects of D. collettii, could reduce the serum uric acid level in a hyperuricemic mouse via regulation of urate transporters. METHODS: Chronic hyperuricemia model was established by combine administration of adenine (100mg/kg) and ethambutol (250mg/kg). In the model group, the serum uric acid (SUA), urine uric acid (UUA) volume, and 24-h UUA values increased significantly, while the uric acid clearance rate (CUr) and creatinine clearance rate (CCr) values decreased. Further, the model groups showed significantly lower expression of organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) and significantly higher expression of renal tubular urate transporter 1 (URAT1), glucose transporter 9 (GLUT9) and URAT1 mRNA than the normal control group. RESULTS: Saponins administration was found to have a dose-dependent effect, as evidenced by the increase in the 24-h UUA, CUr and CCr values; the decrease in SUA; the decrease in the renal expression of URAT1 mRNA and URAT1 and GLUT9 proteins; and the increase in the renal expression of the OAT1 and OAT3 proteins. CONCLUSION: The saponins extracted from D. collettii rhizomes had an obvious anti-hyperuricemic effect through downregulation of the URAT1 mRNA and the URAT1 and GLUT9 proteins and upregulation of the OAT1 and OAT3 proteins.

[Effect of total saponin of Dioscorea on chronic hyperuricemia and expression of URAT1 in rats].

OBJECTIVE: To study the preventive and therapeutic effects of total saponin of Dioscorea (TSD) on chronic hyperuricemia, and its effect on urate transporter 1 (URAT1) in rats. METHOD: Ninety male rats were randomly divided into 6 groups: the normal group, the model group, TSD high-, medium- and low-dose (300, 100, 30 mg x kg(-1)) groups and the benzbromarone (10 mg x kg(-1)) group. Potassium oxonate and ethambutol were adopted to establish the chronic hyperuricemia model Since the third week, all the rats were intragastrically administered with drugs for 4 weeks, once a day, in order to determine their uric acid in serum and urine, uric acid excretion and xanthine oxidase (XOD). URAT1 mRNA and URAT1 protein expression in rat renal tubular cells were determined by RT-PCR and immunohistochemistry method respectively. RESULT: Serum uric acid level of the model group increased significantly, while uric acid excretion decreased, with high expressions of renal URAT1 mRNA and URAT1 protein. TSD could dose-dependently reduce the serum uric acid level of chronic hyperuricemia rats, increase the concentration of uric acid and uric acid excretion in urine, and reduce renal URAT1 mRNA and URAT1 protein expression. Its effects were similar with that of benzbromarone, but with no significant effect on XOD and urinary volume of chronic hyperuricemia rats. CONCLUSION: TSD has an obvious effect of anti-hyperuricemia It may reduce the reabsorption of uric acid by inhibiting the high expression of rat renal URAT1.