Advances in gross tumor target volume determination in radiotherapy for patients with hepatocellular carcinoma.

Hepatocellular Carcinoma (HCC) is one of the most common malignant neoplasms. With the advancement of technology, the precision of radiotherapy (RT) for HCC has considerably increased, and it is an indispensable modality in the comprehensive management of HCC. Some RT techniques increase the radiation dose to HCC, which decreases the radiation dose delivered to the surrounding normal liver tissue. This approach significantly improves the efficacy of HCC treatment and reduces the incidence of Radiation-induced Liver Disease (RILD). Clear imaging and precise determination of the Gross Target Volume (GTV) are prerequisites of precise RT of HCC. The main hindrances in determining the HCC GTV include indistinct tumor boundaries on imaging and the impact on respiratory motion. The integration of multimodal imaging, four-dimensional imaging, and artificial intelligence (AI) techniques can help overcome challenges for HCC GTV. In this article, the advancements in medical imaging and precise determination for HCC GTV have been reviewed, providing a framework for the precise RT of HCC.

Advances in determining the gross tumor target volume for radiotherapy of brain metastases.

Brain metastases (BMs) are the most prevalent intracranial malignant tumors in adults and are the leading cause of mortality attributed to malignant brain diseases. Radiotherapy (RT) plays a critical role in the treatment of BMs, with local RT techniques such as stereotactic radiosurgery (SRS)/stereotactic body radiotherapy (SBRT) showing remarkable therapeutic effectiveness. The precise determination of gross tumor target volume (GTV) is crucial for ensuring the effectiveness of SRS/SBRT. Multimodal imaging techniques such as CT, MRI, and PET are extensively used for the diagnosis of BMs and GTV determination. With the development of functional imaging and artificial intelligence (AI) technology, there are more innovative ways to determine GTV for BMs, which significantly improve the accuracy and efficiency of the determination. This article provides an overview of the progress in GTV determination for RT in BMs.

The effect of time-delayed contrast-enhanced scanning in determining the gross tumor target volume of large-volume brain metastases.

BACKGROUND AND PURPOSE: To assess the variation of large-volume brain metastases (BMs) boundaries and shapes using enhanced magnetic resonance (MR) scanning with different delay times and to provide a basis for determining the gross tumor target volume (GTV) for radiotherapy of BMs. MATERIALS AND METHODS: We prospectively enrolled 155 patients initially diagnosed with BMs (561 lesions > 1 cm). Contrast-enhanced (CE) T1-weighted imaging scans were performed 1, 3, 5, 10, 18, and 20 min after gadolinium-based contrast agent injection and GTVs were determined as GTV-1min, GTV-3min, GTV-5min, GTV-10min, GTV-18min, and GTV-20min, respectively, which were subsequently fused in different phases. Fusion of the six GTVs was defined as GTV-total, which was set as the reference GTV. The volume, shape, and signal intensity of the GTVs and brain white matter (BWM) were compared at different delay times. RESULTS: GTV-3min, GTV-5min, GTV-10min, GTV-18min, and GTV-20min volumes increased by 2.2 %, 3.8 %, 6.5 %, 9.5 %, and 10.6 %, respectively (P < 0.05) compared with GTV-1min. Compared with GTV-total, GTV-1min, GTV-3min, GTV-5min, GTV-10min, GTV-18min, and GTV-20min volumes reduced by 25.4 %, 22.1 %, 18.7 %, 15.0 %, 11.2 %, and 10.3 %, respectively (P < 0.05). Compared with GTV-total, 29 (51.8 %) fused GTVs had a volume reduction rate < 5 %, 45 (80.4 %) had a Dice similarity coefficient > 0.95, and all contained GTV-10min, GTV-18min or GTV-20min. The signal intensity ratio between the GTV and BWM peaked at 5 min (0.351 ± 0.24). CONCLUSION: Enhanced MR scans with different delay times show significant differences in the boundaries and shapes of large-volume BMs, and time-delayed multi-phase CE scanning should be used in GTV determination, with time phases ≥ 10 min being mandatory.

The role of peripheral white blood cell counts in the association between central adiposity and glycemic status.

AIMS: Although central adiposity is a well-known risk factor for diabetes, the underlying mechanism remains unclear. The aim of this study was to explore the potential mediation role of circulating WBC counts in the association between central adiposity and the risk of diabetes. MATERIALS AND METHODS: A cross-sectional study was conducted using data from the Fuqing cohort study, which included 6,613 participants aged 35-75 years. Logistic regression analysis and Spearman's rank correlation analysis were used to examine the relationships between waist-to-hip ratio, WBC counts and glycemic status. Both simple and parallel multiple mediation models were used to explore the potential mediation effects of WBCs on the association of waist-to-hip ratio with diabetes. RESULTS: The study revealed a positive relationship between waist-to-hip ratio and risk of prediabetes (OR = 1.53; 95% CI, 1.35 to 1.74) and diabetes (OR = 2.89; 95% CI, 2.45 to 3.40). Moreover, elevated peripheral WBC counts were associated with both central adiposity and worsening glycemic status (P < 0.05). The mediation analysis with single mediators demonstrated that there is a significant indirect effect of central adiposity on prediabetes risk through total WBC count, neutrophil count, lymphocyte count, and monocyte count; the proportions mediated were 9.92%, 6.98%, 6.07%, and 3.84%, respectively. Additionally, total WBC count, neutrophil count, lymphocyte count, monocyte count and basophil count mediated 11.79%, 11.51%, 6.29%, 4.78%, and 1.76%, respectively, of the association between central adiposity and diabetes. In the parallel multiple mediation model using all five types of WBC as mediators simultaneously, a significant indirect effect (OR = 1.09; 95% CI, 1.06 to 1.14) were observed, with a mediated proportion of 12.77%. CONCLUSIONS: Central adiposity was independently associated with an elevated risk of diabetes in a Chinese adult population; levels of circulating WBC may contribute to its underlying mechanisms.

Synthesis and structural optimization of oncolytic peptide LTX-315.

Oncolytic peptides represented potential novel candidates for anticancer treatments especially drug-resistant cancer cell lines. One of the most promising and extensively studied is LTX-315, which is considered as the first in class oncolytic peptide and has entered phase I/II clinical trials. Nevertheless, the shortcomings including poor proteolytic stability, moderate anticancer durability and high synthesis costs may hinder the widespread clinical applications of LTX-315. In order to reduce the synthesis costs, as well as develop derivatives possessing both high protease-stability and durable anticancer efficiency, twenty LTX-315-based derived-peptides were designed and efficiently synthesized. Especially, through solid-phase S-alkylation, as well as the optimized peptide cleavage condition, the derived peptides could be prepared with drastically reduced synthesis cost. The in vitro anticancer efficiency, serum stability, anticancer durability, anti-migration activity, and hemolysis effect were systematically investigated. It was found that derived peptide MS-13 exhibited comparable anticancer efficiency and durability to those of LTX-315. Strikingly, the D-type peptide MS-20, which is the enantiomer of MS-13, was demonstrated to possess significantly high proteolytic stability and sustained anticancer durability. In general, the cost-effective synthesis and stability-guided structural optimizations were conducted on LTX-315, affording the highly hydrolysis resistant MS-20 which possessed durable anticancer activity. Meanwhile, this study also provided a reliable reference for the future optimization of anticancer peptides through the solid-phase S-alkylation and L-type to D-type amino acid substitutions.

Comparison of chemotherapy and chidamide combined with chemotherapy in patients with untreated angioimmunoblastic T-cell lymphoma.

Background: Angioimmunoblastic T-cell lymphoma (AITL) is characterized by high recurrence rates and poor prognosis, and effective first-line treatment is lacking. Recently, histone deacetylase inhibitors (HDACi), such as chidamide, have been found to induce durable remissions in AITL patients. Methods: Patients with untreated AITL from March 2015 to March 2023 were retrospectively collected and divided into chemotherapy (ChT) group and chidamide combined with chemotherapy (C-ChT) group based on the first-line treatment received. The comparison of efficacy and safety between the two groups was conducted. Results: 86 patients with newly diagnosed AITL were enrolled, in which 35 patients were in the ChT group and 51 in the C-ChT group. The objective response rate (ORR) of C-ChT group was significantly higher than that of ChT group (84.3% vs. 60%, P= 0.011), and had superior progression-free survival (PFS) (27 months vs. 12 months, P= 0.025). However, no significant difference in overall survival (OS) was observed between the two groups (P= 0.225). In addition, the responding patients who received autologous stem cell transplantation (ASCT) had superior PFS compared to those who did not (P= 0.015). Conclusions: Compared with ChT regimen, C-ChT regimen was well tolerated and had superior ORR and PFS in patients with untreated AITL. ASCT may contribute to longer PFS in remission patients.

d-type peptides based fluorescent probes for "turn on" sensing of heparin.

Developing "turn on" fluorescent probes was desirable for the detection of the effective anticoagulant agent heparin in clinical applications. Through combining the aggregation induced emission (AIE) fluorogen tetraphenylethene (TPE) and heparin specific binding peptide AG73, the promising "turn on" fluorescent probe TPE-1 has been developed. Nevertheless, although TPE-1 could achieve the sensitive and selective detection of heparin, the low proteolytic stability and undesirable poor solubility may limit its widespread applications. In this study, seven TPE-1 derived fluorescent probes were rationally designed, efficiently synthesized and evaluated. The stability and water solubility were systematically estimated. Especially, to achieve real-time monitoring of proteolytic stability, the novel Abz/Dnp-based "turn on" probes that employ the internally quenched fluorescent (IQF) mechanism were designed and synthesized. Moreover, the detection ability of synthetic fluorescent probes for heparin were systematically evaluated. Importantly, the performance of d-type peptide fluorescent probe XH-6 indicated that d-type amino acid substitutions could significantly improve the proteolytic stability without compromising its ability of heparin sensing, and attaching solubilizing tag 2-(2-aminoethoxy) ethoxy) acid (AEEA) could greatly enhance the solubility. Collectively, this study not only established practical strategies to improve both the water solubility and proteolytic stability of "turn on" fluorescent probes for heparin sensing, but also provided valuable references for the subsequent development of enzymatic hydrolysis-resistant d-type peptides based fluorescent probes.

Effects of MEK1/2 inhibitor U0126 on FGF10-enhanced buffalo oocyte maturation in vitro.

Fibroblast growth factor 10 (FGF10) plays critical roles in oocyte maturation and embryonic development; however, the specific pathway by which FGF10 promotes in vitro maturation of buffalo oocytes remains elusive. The present study was aimed at investigating the mechanism underlying effects of the FGF10-mediated extracellular regulated protein kinases (ERK) pathway on oocyte maturation and embryonic development in vitro. MEK1/2 (mitogen-activated protein kinase kinase) inhibitor U0126, alone or in combination with FGF10, was added to the maturation culture medium during maturation of the cumulus oocyte complex. Morphological observations, orcein staining, apoptosis detection, and quantitative real-time PCR were performed to evaluate oocyte maturation, embryonic development, and gene expression. U0126 affected oocyte maturation and embryonic development in vitro by substantially reducing the nuclear maturation of oocytes and expansion of the cumulus while increasing the apoptosis of cumulus cells. However, it did not have a considerable effect on glucose metabolism. These findings suggest that blocking the MEK/ERK pathway is detrimental to the maturation and embryonic development potential of buffalo oocytes. Overall, FGF10 may regulate the nuclear maturation of oocytes and cumulus cell expansion and apoptosis but not glucose metabolism through the MEK/ERK pathway. Our findings indicate that FGF10 regulates resumption of meiosis and expansion and survival of cumulus cells via MEK/ERK signaling during in vitro maturation of buffalo cumulus oocyte complexes. Elucidation of the mechanism of action of FGF10 and insights into oocyte maturation should advance buffalo breeding. Further studies should examine whether enhancement of MEK/ERK signaling improves embryonic development in buffalo.

The ratio of systolic and diastolic pressure is associated with carotid and femoral atherosclerosis.

Background: Although the impact of hypertension on carotid intima-media thickness (IMT) and plaques has been well established, its association with femoral IMT and plaques has not been extensively examined. In addition, the role of the ratio of systolic and diastolic pressure (SDR) in the subclinical atherosclerosis (AS) risk remains unknown. We assessed the relationship between SDR and carotid and femoral AS in a general population. Methods: A total of 7,263 participants aged 35-74 years enrolled from January 2019 to June 2021 in a southeast region of China were included in a cross-sectional study. Systolic and diastolic blood pressure (SBP and DBP) were used to define SDR. Ultrasonography was applied to assess the AS, including thickened IMT (TIMT) and plaque in the carotid and femoral arteries. Logistic regression and restricted cubic spline (RCS) models were the main approaches. Results: The prevalence of TIMT, plaque, and AS were 17.3%, 12.4%, and 22.7% in the carotid artery; 15.2%, 10.7%, and 19.5% in the femoral artery; and 23.8%, 17.9% and 30.0% in either the carotid or femoral artery, respectively. Multivariable logistic regression analysis found a significant positive association between high-tertile SDR and the higher risk of overall TIMT (OR = 1.28, 95% CI = 1.10-1.49), plaques (OR = 1.36, 95%CI = 1.16-1.61), or AS (OR = 1.36, 95% CI = 1.17-1.57), especially in the carotid artery. RCS analysis further revealed the observed positive associations were linear. Further analyses showed that as compared to the low-tertile SDR and non-hypertension group, high-tertile SDR was associated with increased risks of overall and carotid TIMT, plaques, or AS in both groups with or without hypertension. Conclusions: SDR is related to a higher risk of subclinical AS, regardless of hypertension or not, suggesting that as a readily obtainable index, SDR can contribute to providing additional predictive value for AS.

A comparative analysis of the clinical pregnancy and perinatal outcomes between oocyte vitrification and embryo vitrification based on the propensity score matching method.

PURPOSE: This study investigated the safety and effectiveness of oocyte vitrification by comparing the clinical pregnancy and perinatal outcomes between transfer cycles of vitrified oocytes and those of vitrified embryos. METHODS: A retrospective cohort study was conducted to analyze the clinical data of patients who underwent cleavage-stage embryo transfer at the Department of Reproductive Medicine between January 2011 and June 2021. Seventy-seven transfer cycles of fresh cleavage-stage embryos developed from vitrified-thawed oocytes (oocyte vitrification group) and 2170 transfer cycles of vitrified-thawed cleavage-stage embryos developed from fresh oocytes (embryo vitrification group) were included. Further, 293 cases were selected from the embryo vitrification group after applying propensity score matching at 1:4. The primary outcomes were miscarriage rate, live birth rate, and neonatal birth weight. RESULTS: No statistically significant differences were observed in the baseline data, pregnancy, perinatal outcomes, or neonatal outcomes for either singleton or twin births between the two groups after matching. Backwards stepwise regression was used to analyze the length of gestation. The age of female participants (ß = - 0.410, 95% CI = - 1.339 ~ - 0.620, P < 0.001) had a statistically significant effect. CONCLUSION: Oocyte vitrification results in similar clinical pregnancy and perinatal outcomes as does embryo vitrification; hence, it is a relatively safe assisted reproductive technique.

Hippocampal sparing in whole-brain radiotherapy for brain metastases: controversy, technology and the future.

Whole-brain radiotherapy (WBRT) plays an irreplaceable role in the treatment of brain metastases (BMs), but cognitive decline after WBRT seriously affects patients' quality of life. The development of cognitive dysfunction is closely related to hippocampal injury, but standardized criteria for predicting hippocampal injury and dose limits for hippocampal protection have not yet been developed. This review systematically reviews the clinical efficacy of hippocampal avoidance - WBRT (HA-WBRT), the controversy over dose limits, common methods and characteristics of hippocampal imaging and segmentation, differences in hippocampal protection by common radiotherapy (RT) techniques, and the application of artificial intelligence (AI) and radiomic techniques for hippocampal protection. In the future, the application of new techniques and methods can improve the consistency of hippocampal dose limit determination and the prediction of the occurrence of cognitive dysfunction in WBRT patients, avoiding the occurrence of cognitive dysfunction in patients and thus benefiting more patients with BMs.

The association between serum magnesium and chronic kidney disease in Chinese adults: a cross-sectional study.

BACKGROUND: Magnesium (Mg) is both an essential macro-element and a known catalyst, and it plays a vital role in various physiological activities and mechanisms in relation to chronic kidney disease (CKD). However, epidemiological evidence involving this is limited and not entirely consistent. This study aims to explore the association of serum Mg concentrations with the risk of CKD among general Chinese adults. METHODS: A total of 8,277 Chinese adults were included in the wave of 2009 from the China Health and Nutrition Survey (CHNS). The primary outcome was the risk of CKD, which was defined as the estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Multivariable logistic regression model was used to examine the relationship of serum Mg concentrations with the risk of CKD. RESULTS: Included were 8,277 individuals, with an overall CKD prevalence of 11.8% (n = 977). Compared with the first quartile of serum Mg, the multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for participants in the second, third, and fourth quartiles of serum Mg were 0.74 (0.58, 0.93), 0.87 (0.69, 1.11) and 1.29 (1.03, 1.61), respectively. Similar results were observed in our several sensitivity analyses. Restricted cubic spline analysis demonstrated a nonlinear (similar "J"-shaped) association between serum Mg concentrations and the risk of CKD (Pnonlinearity <0.001), with a threshold at around a serum Mg value of 2.2 mg/dL. CONCLUSIONS: Our results suggested a similar "J"-shaped association between serum Mg concentration and the risk of CKD among Chinese adults. Further large prospective studies are needed to verify these findings.

Three Rounds of Stability-Guided Optimization and Systematical Evaluation of Oncolytic Peptide LTX-315.

Oncolytic peptides represent promising novel candidates for anticancer treatments. In our efforts to develop oncolytic peptides possessing both high protease stability and durable anticancer efficiency, three rounds of optimization were conducted on the first-in-class oncolytic peptide LTX-315. The robust synthetic method, in vitro and in vivo anticancer activity, and anticancer mechanism were investigated. The D-type peptides represented by FXY-12 possessed significantly improved proteolytic stability and sustained anticancer efficiency. Strikingly, the novel hybrid peptide FXY-30, containing one FXY-12 and two camptothecin moieties, exhibited the most potent in vitro and in vivo anticancer activities. The mechanism explorations indicated that FXY-30 exhibited rapid membranolytic effects and induced severe DNA double-strand breaks to trigger cell apoptosis. Collectively, this study not only established robust strategies to improve the stability and anticancer potential of oncolytic peptides but also provided valuable references for the future development of D-type peptides-based hybrid anticancer chemotherapeutics.

Associations between body composition profile and hypertension in different fatty liver phenotypes.

Background: It is currently unclear whether and how the association between body composition and hypertension varies based on the presence and severity of fatty liver disease (FLD). Methods: FLD was diagnosed using ultrasonography among 6,358 participants. The association between body composition and hypertension was analyzed separately in the whole population, as well as in subgroups of non-FLD, mild FLD, and moderate/severe FLD populations, respectively. The mediation effect of FLD in their association was explored. Results: Fat-related anthropometric measurements and lipid metabolism indicators were positively associated with hypertension in both the whole population and the non-FLD subgroup. The strength of this association was slightly reduced in the mild FLD subgroup. Notably, only waist-to-hip ratio and waist-to-height ratio showed significant associations with hypertension in the moderate/severe FLD subgroup. Furthermore, FLD accounted for 17.26% to 38.90% of the association between multiple body composition indicators and the risk of hypertension. Conclusions: The association between body composition and hypertension becomes gradually weaker as FLD becomes more severe. FLD plays a significant mediating role in their association.

Do pilot free trade zones promote green innovation efficiency in enterprises? -Evidence from listed companies in China.

The establishment of the China Pilot Free Trade Zone complies with the concept of sustainable development, and its construction can not only realize trade liberalization and facilitation but also activate the green innovation momentum of enterprises to help solve China's current dilemma of sustainable development and economic growth. This paper is the first to consider the impact of the establishment of the pilot free trade zone from the perspective of enterprise green innovation efficiency, providing a direct answer to the key question of whether the construction of the pilot free trade zone can truly serve the high-quality development of the economy in the new era, and enriching the theoretical research on the enterprise green innovation efficiency macro-drivers related theoretical research. In addition, this paper uses the super-efficient EBM-GML model to measure the level of green innovation efficiency of enterprises, on the basis of this, it adopts the multi-stage differences-in-differences method used to evaluate the impact of the establishment of the pilot free trade zone on the green innovation efficiency of enterprises. According to the benchmark regression results, the establishment of the pilot free trade zone has promoted the degree of green innovation efficiency of enterprises, and this promotion effect is sustainable. This conclusion was validated by robustness tests. Heterogeneity testing confirms that the pilot free trade zone has a significant influence on the green innovation efficiency of enterprises in heavy pollution industries, non-state-owned enterprises and patent-intensive enterprises. With the enhancement of environmental regulations, the green innovation efficiency of enterprises shows significant improvements. The analysis of the transmission mechanism shows that the pilot free trade zone influences the green innovation efficiency of enterprises primarily through the cost reduction effect, tax incentive effect, and reverse technology spillover effect. This study clarifies whether the policy of the pilot free trade zone can boost the green innovation efficiency of enterprises, and provides useful insight for further implementing the strategy of opening up to the world and promoting high-quality economic growth.

Shift in prevalence and systemic inflammation levels from NAFLD to MAFLD: a population-based cross-sectional study.

BACKGROUND: Variations in the prevalence and systemic inflammatory (SI) status between non-alcoholic fatty liver disease (NAFLD) and newly defined metabolic dysfunction-associated fatty liver disease (MAFLD) have only been reported by few studies. Hence, this study aimed to compile data on the prevalence and the systemic inflammation levels of MAFLD and NAFLD in a general population from Southeast China was summarized to explore the potential effect of the transformation of disease definition. METHODS: A total of 6718 general population participants aged 35-75 were enrolled. Logistic regression and restricted cubic spline (RCS) models were used to examine the relationship between 15 SI indicators and NAFLD and MAFLD. The predicted values of MAFLD and NAFLD were analyzed using the receiver operating characteristic (ROC) curve. RESULTS: The prevalence of MAFLD and NAFLD was 34.7% and 32.4%, respectively. Their overlapping rate was 89.7%, while only 8.3% and 1.9% of participants were MAFLD-only and NAFLD-only. Among three FLD groups, the MAFLD-only group had the highest levels of 8 SI indicators, including CRP, WBC, LYMPH, NEUT, MONO, ALB, NLR, and SIRI. The non-FLD group had the lower levels of all 15 SI indicators compared with all FLD subgroups. The odds ratios (ORs) of 10 SI indicators were significant in both multivariable-adjusted logistic regression and RCS analyses of MAFLD or NAFLD, including CRP, WBC, LYMPH, NEUT, MONO, ALB, PLR, LMR, ALI and CA. ROC analysis showed that the AUC values of all SI were lower than 0.7 in both MAFLD and NAFLD. CONCLUSIONS: MAFLD could cover more FLD than NAFLD, and the MAFLD-only group had a more severe inflammation status, whereas the NAFLD-only exhibited lower levels. Moreover, there was not a high AUC and a high sensitivity of SI indicators, suggesting that SI indicators are not good indicators to diagnose NAFLD/MAFLD.

Aesthetic Enhancement of the Gonial Angle and Inferior Mandibular Border in the Chinese Population.

BACKGROUND: The current absence of a standardized mandibular body osteotomy design poses challenges in surgical planning. Traditional approaches may not suit patients with wider anterior mandibles, potentially resulting in unsatisfactory outcomes. Addressing this issue requires a rational design that combines mandibular angle and body osteotomies for improved clinical practice. OBJECTIVES: In this retrospective cohort study we aimed to analyze mandibular computed tomography (CT) data with digital methods. The goal was to establish an integrated osteotomy design for both mandibular angle and body procedures and classify prevalent mandibular types in the Chinese Han population for surgical guidance. METHODS: Included were 89 patients who underwent mandibular angle osteotomy without genioplasty between 2016 and 2022 at Peking University Third Hospital. Mimics 21.0 software facilitated CT data reconstruction and osteotomy planning. Postoperative effects were assessed through imaging, complications, and surveys, leading to mandibular type classification. RESULTS: Mandibular angles were categorized by 3 types, based on osteotomy range. Type I involved mandibular body osteotomy only, type II mandibular angle osteotomy only, and type III both mandibular angle and body osteotomies. Distribution within the cohort was 2.25%, 8.99%, and 88.76% for types I, II, and III respectively. Patient satisfaction was high, with minor and major complications at 47.19% and 1.12% by Clavien-Dindo classification. CONCLUSIONS: Utilizing Mimics software, we established an integrated osteotomy design and categorized mandibular types. Findings offer valuable guidance for mandibular angle surgery and contribute to understanding of Asian mandibular morphology.

Novel Sulfonylurea-Based NLRP3 Inflammasome Inhibitor for Efficient Treatment of Nonalcoholic Steatohepatitis, Endotoxic Shock, and Colitis.

The NLRP3 inflammasome is a critical component of innate immunity involved in the pathophysiology of various inflammatory diseases. In this study, we designed and synthesized a series of NLRP3 inflammasome inhibitors based on MCC950. Specifically, we optimized the furan moiety, which is considered to be potentially associated with drug-induced liver injury. The representative inhibitor N14, 4-(2-(dimethylamino)ethyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonamide, not only maintains the NLRP3 inhibitory activity of MCC950 with IC50 of 25 nM but also demonstrates improved tolerability in human hepatic cells line and mouse primary hepatocytes. In addition, N14 exhibits superior pharmacokinetic properties, with an oral bioavailability of 85.2%. In vivo studies demonstrate that N14 is more effective than MCC950 in multiple NLRP3-related animal model diseases, including nonalcoholic steatohepatitis, lethal septic shock, and colitis. Our research has provided a lead compound that directly targets the NLRP3 inflammasome and can be developed as a novel therapeutic candidate for NLRP3-driven diseases.

Carrageenan as a macromolecular crowding agent in human umbilical cord derived mesenchymal stromal cell culture.

Cell sheet tissue engineering requires prolonged in vitro culture for the development of implantable devices. Unfortunately, lengthy in vitro culture is associated with cell phenotype loss and substantially higher cost of goods, which collectively hinder clinical translation and commercialisation of tissue engineered medicines. Although macromolecular crowding has been shown to enhance and accelerate extracellular matrix deposition, whilst maintaining cellular phenotype, the optimal macromolecular crowding agent still remains elusive. Herein, we evaluated the biophysical properties of seven different carrageenan molecules at five different concentrations and their effect on human umbilical cord-derived mesenchymal stromal cell morphology, viability, metabolic activity, proliferation, extracellular matrix deposition and surface marker expression. All types of carrageenan (CR) assessed demonstrated a hydrodynamic radius increase as a function of increasing concentration; high polydispersity; and negative charge. Two iota CRs were excluded from further analysis due to poor solubility in cell culture. Among the remaining five carrageenans, the lambda medium viscosity type at concentrations of 10 and 50 µg/ml did not affect cell morphology, viability, metabolic activity, proliferation and expression of surface markers and significantly increased the deposition of collagen types I, III and IV, fibronectin and laminin. Our data highlight the potential of lambda medium viscosity carrageenan as a macromolecular crowding agent for the accelerated development of functional tissue engineered medicines.