Sevoflurane impedes neuropathic pain by maintaining endoplasmic reticulum stress and oxidative stress homeostasis through inhibiting the activation of the PLCγ/CaMKII/IP3R signaling pathway.

OBJECTIVE: To investigate the effect of sevoflurane on neuropathic pain induced by chronic constriction injury (CCI) of sciatic nerve in mice, and to elucidate its mechanism by animal experiments. METHODS AND RESULTS: Thirty-two C57BL/6 mice were randomly divided into four groups: Sham group, Model group, Control group and Sevoflurane group. First, a mouse model of neuropathic pain was established. Then, the mice in each group were killed on Day 14 after operation to harvest the enlarged lumbosacral spinal cord. In contrast with the Model group, the Sevoflurane group displayed a significantly increased paw withdrawal mechanical threshold (PWMT) and significantly prolonged paw withdrawal thermal latency (PWTL) from Day 5 after operation. The morphological changes of lumbosacral spinal cord were observed by hematoxylin-eosin (HE) staining and transmission electron microscopy. Pathological results showed that sevoflurane reduced nuclear pyknosis in lumbosacral spinal cord tissue, with a large number of mitochondrial crista disappearance and mitochondrial swelling. The results of Western blotting showed that sevoflurane significantly decreased the protein expressions of phosphorylated phospholipase Cγ (p-PLCγ), phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII) and phosphorylated inositol 1,4,5-triphosphate receptor (p-IP3R), and reduced the protein expressions of endoplasmic reticulum (ER) stress proteins glucose-regulated protein 78 (GRP78) and GRP94, oxidative stress-related proteins P22 and P47 and inflammatory factors nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), interleukin-1 ß (IL-1ß), and tumor necrosis factor-α (TNF-α). CONCLUSIONS: Sevoflurane inhibits neuropathic pain by maintaining ER stress and oxidative stress homeostasis through inhibiting the activation of the PLCγ/CaMKII/IP3R signaling pathway.

Effects of textured insoles on dynamic balance and ankle muscle activity in soccer players with and without chronic ankle instability.

BACKGROUND: Chronic ankle instability (CAI) poses challenges in sports. Textured insoles (TI) are a promising intervention for enhancing dynamic balance in CAI athletes. This study aimed to investigate the effects of TI on dynamic balance performance and ankle muscle activity in soccer players with and without CAI. METHODS: Thirty-eight soccer players (19 CAI, 19 non-CAI) participated. Participants performed a modified star excursion balance test (mSEBT) while wearing TI and standard insoles (SI). The %SEBT reach distance and electromyography (EMG) activity of tibialis anterior (TA), medial gastrocnemius (MG), and peroneus longus (PL) were measured during maximum reached in each direction of the mSEBT. RESULTS: No significant effects or interactions were found between ankle conditions (CAI vs. non-CAI) or insole types (TI vs. SI) on %SEBT reach. However, CAI players showed greater MG activity in posteromedial and posterolateral direction (P=0.04, P=0.01). CONCLUSIONS: Overall, the application of TI did not have immediate effects on dynamic balance performance or ankle muscle activity in either CAI or non-CAI soccer players. Nonetheless, CAI players seemed to employ a different ankle strategy involving the MG muscle, possibly to control stability during dynamic movement, particularly in the posteromedial and posterolateral directions.

MAMs and Mitochondrial Quality Control: Overview and Their Role in Alzheimer's Disease.

Alzheimer's disease (AD) represents the most widespread neurodegenerative disorder, distinguished by a gradual onset and slow progression, presenting a substantial challenge to global public health. The mitochondrial-associated membrane (MAMs) functions as a crucial center for signal transduction and material transport between mitochondria and the endoplasmic reticulum, playing a pivotal role in various pathological mechanisms of AD. The dysregulation of mitochondrial quality control systems is considered a fundamental factor in the development of AD, leading to mitochondrial dysfunction and subsequent neurodegenerative events. Recent studies have emphasized the role of MAMs in regulating mitochondrial quality control. This review will delve into the molecular mechanisms underlying the imbalance in mitochondrial quality control in AD and provide a comprehensive overview of the role of MAMs in regulating mitochondrial quality control.

Class-Incremental Learning: A Survey.

Deep models, e.g., CNNs and Vision Transformers, have achieved impressive achievements in many vision tasks in the closed world. However, novel classes emerge from time to time in our ever-changing world, requiring a learning system to acquire new knowledge continually. Class-Incremental Learning (CIL) enables the learner to incorporate the knowledge of new classes incrementally and build a universal classifier among all seen classes. Correspondingly, when directly training the model with new class instances, a fatal problem occurs - the model tends to catastrophically forget the characteristics of former ones, and its performance drastically degrades. There have been numerous efforts to tackle catastrophic forgetting in the machine learning community. In this paper, we survey comprehensively recent advances in class-incremental learning and summarize these methods from several aspects. We also provide a rigorous and unified evaluation of 17 methods in benchmark image classification tasks to find out the characteristics of different algorithms empirically. Furthermore, we notice that the current comparison protocol ignores the influence of memory budget in model storage, which may result in unfair comparison and biased results. Hence, we advocate fair comparison by aligning the memory budget in evaluation, as well as several memory-agnostic performance measures. The source code is available at https://github.com/zhoudw-zdw/CIL_Survey/.

Membrane protein MHZ3 regulates the on-off switch of ethylene signaling in rice.

Ethylene regulates plant growth, development, and stress adaptation. However, the early signaling events following ethylene perception, particularly in the regulation of ethylene receptor/CTRs (CONSTITUTIVE TRIPLE RESPONSE) complex, remains less understood. Here, utilizing the rapid phospho-shift of rice OsCTR2 in response to ethylene as a sensitive readout for signal activation, we revealed that MHZ3, previously identified as a stabilizer of ETHYLENE INSENSITIVE 2 (OsEIN2), is crucial for maintaining OsCTR2 phosphorylation. Genetically, both functional MHZ3 and ethylene receptors prove essential for OsCTR2 phosphorylation. MHZ3 physically interacts with both subfamily I and II ethylene receptors, e.g., OsERS2 and OsETR2 respectively, stabilizing their association with OsCTR2 and thereby maintaining OsCTR2 activity. Ethylene treatment disrupts the interactions within the protein complex MHZ3/receptors/OsCTR2, reducing OsCTR2 phosphorylation and initiating downstream signaling. Our study unveils the dual role of MHZ3 in fine-tuning ethylene signaling activation, providing insights into the initial stages of the ethylene signaling cascade.

VEGFA locus amplification potentially predicts a favorable prognosis in gastric adenocarcinoma.

Gastric adenocarcinoma harbors a range of genetic and epigenetic alterations, including alterations in DNA copy number. However, the key genes that promote the development and progression of gastric adenocarcinoma remain unknown. To identify the key genes amplified in gastric adenocarcinoma, we performed array comparative genomic hybridization on formalin-fixed paraffin-embedded samples of surgically resected gastric adenocarcinoma. We detected a relatively wide genomic region of gain containing the vascular endothelial growth factor A (VEGFA) gene locus on chromosome 6p. VEGFA locus amplification in gastric adenocarcinoma was validated by fluorescence in situ hybridization. To assess the frequency of VEGFA locus amplification in gastric adenocarcinoma, we conducted multiplex ligation-dependent probe amplification (MLPA) assays using homemade probes designed to target the VEGFA gene locus. Eleven of 54 (20 %) gastric adenocarcinomas with MLPA values above 1.3 were defined as having VEGFA locus amplification. Next, we investigated the effect of VEGFA locus amplification on the clinicopathological characteristics of gastric adenocarcinomas and patient survival. VEGFA locus amplification demonstrated a significantly close relationship with pathological intestinal type and lower rates of venous invasion Furthermore, a Kaplan-Meier analysis showed that patients with VEGFA locus amplification had significantly better overall survival than those without amplification (p = 0.038), particularly in the long-term follow-up period. In conclusion, VEGFA locus amplification can predict modest aggressiveness and good outcomes, suggesting the possibility that it may predict a favorable prognosis in patients with gastric adenocarcinoma.

Construction and Validation of a Nomogram to Identify the Risk of Cavitation in Pulmonary Tuberculosis.

Background: The present study aimed to construct and validate a nomogram based on clinical metrics to identify CPTB. Patients and Methods: The present study retrospectively recruited pulmonary tuberculosis (PTB) patients admitted to Jiashan County First People's Hospital in China from November 2018 to September 2023. PTB patients were classified into the CPTB group and the non-CPTB group based on chest computed tomography findings, and were randomly allocated to the training set (70%) and the validation cohort (30%). The training set and validation set were used to establish and validate nomogram, respectively. Multivariate logistic regression analysis (MLSA) was used to identify the independent risk factors for CPTB in patients with PTB. Statistically significant variables in the MLSA were then used to construct a nomogram predicting CPTB in patients with PTB. The receiver operating characteristic (ROC) curve, calibration curve analysis (CCA), and decision curve analysis (DCA) were used for the evaluation of the nomogram. Results: A total of 293 PTB patients, including 208 in the training set (85 CPTB) and 85 in the validation set (33 CPTB\), were included in this study. Stepwise MLSA showed that sputum smear (≥2+), smoking(yes), glycosylated hemoglobin A1c(HbA1c), hemoglobin (HB), and systemic inflammatory response index (SIRI) were independent risk factors for the development of cavitation in patients with PTB. The nomogram identifying the high-risk CPTB patients was successfully established and showed a strong predictive capacity, with area under the curves (AUCs) of 0.875 (95% CI:0.806-0.909) and 0.848 (95% CI:0.751-0.946) in the training set and validation set respectively. In addition, the CCA and DCA corroborated the nomogram's high level of accuracy and clinical applicability within both the training and validation sets. Conclusion: The constructed nomogram, consisting of sputum smear positivity, smoking, HbA1C, HB, and SIRI, serves as a practical and effective tool for early identification and personalized management of CPTB.

Balance Control Deficits are Associated with Diminished Ankle Force Sense, Not Position Sense, in Athletes with Chronic Ankle Instability.

OBJECTIVES: To compare balance control and ankle proprioception between athletes with and without chronic ankle instability (CAI). A further objective was to explore the relationship between balance control performance and ankle proprioception in athletes with CAI. DESIGN: Cross-sectional study. SETTINGS: Sports Rehabilitation Laboratory. PARTICIPANTS: Eighty-eight recreational athletes (47 CAI and 41 healthy control) were recruited. INTERVENTIONS: No applicable. MAIN OUTCOME MEASURES: Balance control performance was assessed using the sway velocity of the centre of the pressure during the one-leg standing tasks. Ankle proprioception, including joint position sense and force sense, were tested using absolute error (AE) associated with joint position reproduction and force reproduction tasks in four directions, i.e., plantarflexion, dorsiflexion, inversion, and eversion. RESULTS: Athletes with CAI performed significantly worse than those without CAI in balance control tasks. In addition, CAI athletes showed significantly worse joint position sense and force sense in all three movement directions tested (plantarflexion, inversion, and eversion). Correlation analysis showed that the AE of the plantarflexion force sense was significantly moderately correlated with medial-lateral sway velocity in the one-leg standing with eyes open and closed conditions (r = 0.372-0.403, p = 0.006-0.012), and the AE of inversion force sense was significantly moderately correlated with medial-lateral sway velocity in the one-leg standing with eyes open (r = 0.345, p = 0.018) in athletes with CAI, but the joint position sense measures were not (all p > 0.05). CONCLUSIONS: Athletes with CAI showed significantly impaired balance control performance and diminished ankle proprioception. Deficit in force sense was deemed as a moderate predictor of one-leg standing balance control deficits in athletes with dominant-side injury CAI, while ankle position sense may be a small predictor.

Platelet PD-L1 inhibits storage-induced apoptosis by sustaining activation of the AKT signalling pathway.

Platelet apoptosis is irreversible under current storage conditions in blood banks. Studies have shown that programmed cell death ligand 1 (PD-L1) in tumour cells is required for neoplastic progression, tumour recurrence and metastasis by regulating apoptosis. However, whether PD-L1 is involved in storage-induced apoptosis in platelets remains poorly understood. In this study, we explored whether PD-L1 on platelets participated in the regulation of storage-induced apoptosis under blood bank conditions, as well as the underlying mechanism. Several apoptotic events in platelets from humans and PD-L1-knockout mice during storage under blood bank conditions were measured. The mechanism by which storage-induced apoptosis was regulated by platelet-intrinsic PD-L1 signalling was further investigated. Our results showed that PD-L1 in platelets progressively decreased. There was a strong negative correlation between platelet PD-L1 expression and the phosphatidylserine (PS) externalization rate and cleaved caspase-3 level and a positive correlation with anti-apoptosis protein Bcl-xl. Ex vivo, PD-L1-/- platelets stored at 22 °C showed rapid apoptosis via an intrinsic mitochondria-dependent pathway over time. Likewise, inhibiting PD-L1 signalling with BMS-1166 accelerated apoptosis by intrinsic mitochondria-dependent pathway. Coimmunoprecipitation analysis revealed that PD-L1 could bind AKT in platelets, and the binding capacity of both showed a progressive decrease with time. Finally, the decrease in PD-L1 expression levels during storage could be attributed to a complex process of progressive secretion. Therefore, platelet PD-L1 inhibits storage-induced apoptosis by sustaining activation of the AKT signalling pathway, which is expected to become a target for alleviating platelet storage lesions (PSLs) under current blood bank conditions.

Influences of Propofol, Ciprofol and Remimazolam on Dreaming During Anesthesia for Gastrointestinal Endoscopy: A Randomized Double-Blind Parallel-Design Trial.

Purpose: To compare the influences of propofol, ciprofol and remimazolam on dreaming during painless gastrointestinal endoscopy. Methods: This study was a single-center, prospective, parallel-design, double-blind, randomized clinical trial. Between May 2023 and October 2023, patients undergoing elective painless gastrointestinal endoscopy were recruited and randomly allocated into one of the three groups. Demographic data, intraoperative information, incidence of dreaming, insufficient anesthesia and intraoperative awareness, type of dream, patient satisfaction score, adverse events, and improvement of sleep quality were collected. Results: The difference in incidence of dreaming among the three groups was not significant (33.33% vs 48.33% vs 41.67%, p=0.061). The number of patients with intraoperative hypotension in the propofol group was larger than that of the remimazolam group (32 vs 12, p=0.001). However, the cases of intraoperative hypotension between propofol group and ciprofol group or ciprofol group and remimazolam group were comparable (32 vs 22, p=0.122; 22 vs 12, p=0.064). The percentage of insufficient anesthesia between propofol group and remimazolam group was significant (13.33% vs 1.67%, p=0.001), while no statistical difference was detected between propofol group and remimazolam group or ciprofol group and remimazolam group (13.33% vs 5.00%, p=0.025; 5.00% vs 1.67%, p=0.150). The ability of propofol to improve sleep quality at 1st post-examination day was significantly better than that of remimazolam (86.21% vs 72.88%, p=0.015), while it was not significant between propofol group and ciprofol group or ciprofol group and remimazolam group (86.21% vs 80.36%, p=0.236; 72.88% vs. 72.88%, p=0.181). Incidence of intraoperative awareness, intraoperative hypoxia, type of dream, satisfaction score, adverse events during recovery, and sleep improvement on the 7th post-examination day was not significant among the groups. Conclusion: Anesthesia with propofol, ciprofol and remimazolam, respectively, for gastrointestinal endoscopy did not induce statistical difference in the incidence of dreaming, despite that all of them are more likely to induce pleasant dreams.

Lateral Shuffle-Induced Fatigue Effects on Ankle Proprioception and Countermovement Jump Performance.

To determine how lateral shuffling/lateral shuffle (LS) -induced fatigue affects ankle proprioception and countermovement jump (CMJ) performance. Eighteen male college athletes performed 6 modes of a repeated LS protocol with 2 distances (2.5 and 5 m) and 3 speeds (1.6, 1.8, and 2.0 m/s). After LS, ankle inversion proprioception (AIP) was measured using the active movement extent discrimination apparatus (AMEDA). CMJ, blood lactate (BLa), heart rate (HR) and rating of perceived exertion (RPE) were measured before and after LS. The number of changes of direction (CODs) in each protocol was recorded. LS-induced fatigue was evident in BLa, HR and RPE (all p < 0.05), increasing with shorter shuffle distance and faster speed. RM-ANOVA showed a significant distance main effect on both AIP (p < 0.01) and CMJ (p < 0.05), but the speed main effect was only significant for CMJ (p ≤ 0.001), not AIP (p = 0.87). CMJ performance was correlated with BLa, HR and RPE (r values range from -0.62 to -0.32, all p ≤ 0.001). AIP was only correlated with CODs (r = -0.251, p < 0.01). These results suggested that in LS, shorter distance, regardless of speed, was associated with worse AIP, whereas subsequent CMJ performance was affected by both LS distance and speed. Hence, AIP performance was not related to physiological fatigue, but CMJ performance was. Results imply that LS affects processing proprioceptive input and producing muscular output differently, and that these two aspects of neuromuscular control are affected by physiological fatigue to varying degrees. These findings have implications for injury prevention and performance enhancement.

Adolescents and Children Age Estimation Using Machine Learning Based on Pulp and Tooth Volumes on CBCT Images.

OBJECTIVES: To estimate adolescents and children age using stepwise regression and machine learning methods based on the pulp and tooth volumes of the left maxillary central incisor and cuspid on cone beam computed tomography (CBCT) images, and to compare and analyze the estimation results. METHODS: A total of 498 Shanghai Han adolescents and children CBCT images of the oral and maxillofacial regions were collected. The pulp and tooth volumes of the left maxillary central incisor and cuspid were measured and calculated. Three machine learning algorithms (K-nearest neighbor, ridge regression, and decision tree) and stepwise regression were used to establish four age estimation models. The coefficient of determination, mean error, root mean square error, mean square error and mean absolute error were computed and compared. A correlation heatmap was drawn to visualize and the monotonic relationship between parameters was visually analyzed. RESULTS: The K-nearest neighbor model (R2=0.779) and the ridge regression model (R2=0.729) outperformed stepwise regression (R2=0.617), while the decision tree model (R2=0.494) showed poor fitting. The correlation heatmap demonstrated a monotonically negative correlation between age and the parameters including pulp volume, the ratio of pulp volume to hard tissue volume, and the ratio of pulp volume to tooth volume. CONCLUSIONS: Pulp volume and pulp volume proportion are closely related to age. The application of CBCT-based machine learning methods can provide more accurate age estimation results, which lays a foundation for further CBCT-based deep learning dental age estimation research.

A distinct dimer configuration of a diatom Get3 forming a tetrameric complex with its tail-anchored membrane cargo.

BACKGROUND: Most tail-anchored (TA) membrane proteins are delivered to the endoplasmic reticulum through a conserved posttranslational pathway. Although core mechanisms underlying the targeting and insertion of TA proteins are well established in eukaryotes, their role in mediating TA protein biogenesis in plants remains unclear. We reported the crystal structures of algal arsenite transporter 1 (ArsA1), which possesses an approximately 80-kDa monomeric architecture and carries chloroplast-localized TA proteins. However, the mechanistic basis of ArsA2, a Get3 (guided entry of TA proteins 3) homolog in plants, for TA recognition remains unknown. RESULTS: Here, for the first time, we present the crystal structures of the diatom Pt-Get3a that forms a distinct ellipsoid-shaped tetramer in the open (nucleotide-bound) state through crystal packing. Pulldown assay results revealed that only tetrameric Pt-Get3a can bind to TA proteins. The lack of the conserved zinc-coordination CXXC motif in Pt-Get3a potentially leads to the spontaneous formation of a distinct parallelogram-shaped dimeric conformation in solution, suggesting a new dimer state for subsequent tetramerization upon TA targeting. Pt-Get3a nonspecifically binds to different subsets of TA substrates due to the lower hydrophobicity of its α-helical subdomain, which is implicated in TA recognition. CONCLUSIONS: Our study provides new insights into the mechanisms underlying TA protein shielding by tetrameric Get3 during targeting to the diatom's cell membrane.

[Responses of radial growth of Larix principis-rupprechtii at different densities to drought events]. / 不同密度华北落叶松径向生长对干旱事件的响应.

In recent years, a surge in drought occurrences has dramatically impacted tree growth worldwide. We examined the ecological resilience of Larix principis-rupprechtii plantations with varying densities (1950, 2355, and 2595 trees·hm-2) at the Saihanba Mechanical Forest Farm, by extracting the increment cores using the standard dendrochronological method to measure individual-tree basal area increments (BAI) as part of our assessment of ecological resilience, including resistance (Rt), recovery (Rc), and resilience (Rs). The results showed that drought events occurred in 2006-2010, 2015, and 2018. The Rt for L. principis-rupprechtii plantations varied from 0.76 to 2.01 across three drought events, indicating generally high resistance, except for the plantation with 2355 trees·hm-2 during the second dry year (Rt=0.69). The Rt for the plantation with 2595 trees·hm-2 significantly decreased across all drought events, while no significant change was observed in the plantations with 1950 and 2355 trees·hm-2. The Rc showed no differences in response to a single drought event across plantation densities, with a significant upward trend for all the densities with each occurrence of drought event. There was no significant difference in the resilience of different densities of L. principis-rupprechtii to the first drought event, whereas the plantation with 2595 trees·hm-2 exhibited significantly lower Rs during the second and third drought events compared with 1950 and 2355 trees·hm-2, respectively. During the 2015 drought event, plantation with 2595 trees·hm-2 experienced a significant growth decline (radial growth change rate was -26.5%), while no such decline was observed in the plantations with 1950 and 2355 trees·hm-2. Overall, the plantation with 2595 trees·hm-2 demonstrated the lowest resilience to drought events.

Regioselective 1,4-/1,3-Difunctionalization of 1,3-Enynes with Selenosulfonates in Water.

1,4-/1,3-Regioselective bifunctionalization of 1,3-enynes with selenosulfonates in water under catalyst-free conditions for the construction of sulfonyl allene and 1,3-disulfonyl-conjugated dienes respectively have been developed. The reactions feature mild reaction conditions in aqueous solution and remarkable regioselectivity controlled by substrates.

HCl/DMSO/HFIP-Mediated Chlorination of Pyrrolo[2,1-a]isoquinolines and Other Electron-Rich Heteroarenes.

An efficient oxidative chlorination of pyrrolo[2,1-a]isoquinolines has been established using HCl (aq) as the chlorine source and DMSO as the terminal oxidant in HFIP at ambient temperature. A variety of chlorinated pyrrolo[2,1-a]isoquinoline derivatives have been prepared readily in 23 to 99% yields. This chlorination strategy can be expanded to the functionalization of other electron-rich heteroarenes including substituted pyrroles, indoles, and naphthols.

Periarterial or perivenous invasion is an independent indicator of lymph node metastasis in invasive breast carcinoma of no special type.

Pathological diagnosis of breast cancer often includes cases of lymph node metastases without lymphatic or lymphovascular invasion by the primary tumor. In this study, to resolve this discrepancy, we designed a sensitive method to detect lymphatic invasion and correlate it with lymph node metastasis. Elastica van Gieson (EVG) staining and D2-40 immunohistochemistry revealed the abundant distribution of lymphatic vessels around blood vessels in the mammary tissue in close proximity to the elastic fibers around the arteries and veins. Based on the histological location of the blood and lymphatic vessels, we hypothesized that, in breast cancer, perivascular invasion is similar to lymphatic invasion and correlates with the presence of lymph node metastasis. Using EVG staining, perivascular invasion was histologically classified into periarterial invasion (periA), perivenous invasion (periV), and periarterial or perivenous invasion (periA/V). We tested our method and compared it to other methods commonly used for identifying lymphatic invasion in 105 patients with invasive breast carcinoma of no special type (IBC-NST) who received minimal preoperative therapy. The correlation between perivascular invasion and lymph node metastasis in these patients was statistically analyzed, including findings related to lymphatic invasion, such as retractile artifacts and perineural invasion. PeriA, periV, and periA/V showed significant correlations with lymph node metastasis. PeriA/V had high sensitivity and negative predictive value. The odds ratio (OR) for periV was significantly high in the univariate analysis, while the ORs for periA/V, retraction artifacts, and perineural invasion were significantly high in both the univariate and multivariate analyses. In particular, periA/V revealed a strong correlation with lymph node metastasis (OR: 61.8). These findings indicate that the IBC-NST periA/V ratio is a sensitive pointer of lymphatic invasion and could be an independent and reliable indicator of lymph node metastasis.

Advances in Nanotechnology for Enhancing the Solubility and Bioavailability of Poorly Soluble Drugs.

This manuscript offers a comprehensive overview of nanotechnology's impact on the solubility and bioavailability of poorly soluble drugs, with a focus on BCS Class II and IV drugs. We explore various nanoscale drug delivery systems (NDDSs), including lipid-based, polymer-based, nanoemulsions, nanogels, and inorganic carriers. These systems offer improved drug efficacy, targeting, and reduced side effects. Emphasizing the crucial role of nanoparticle size and surface modifications, the review discusses the advancements in NDDSs for enhanced therapeutic outcomes. Challenges such as production cost and safety are acknowledged, yet the potential of NDDSs in transforming drug delivery methods is highlighted. This contribution underscores the importance of nanotechnology in pharmaceutical engineering, suggesting it as a significant advancement for medical applications and patient care.

Nicotinamide phosphoribosyltransferase prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice.

Rationale: Idiopathic pulmonary fibrosis (IPF) is an irreversible, fatal interstitial lung disease lacking specific therapeutics. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the nicotinamide adenine dinucleotide (NAD) salvage biosynthesis pathway and a cytokine, has been previously reported as a biomarker for lung diseases; however, the role of NAMPT in pulmonary fibrosis has not been elucidated. Methods: We identified the NAMPT level changes in pulmonary fibrosis by analyzing public RNA-Seq databases, verified in collected clinical samples and mice pulmonary fibrosis model by Western blotting, qRT-PCR, ELISA and Immunohistochemical staining. We investigated the role and mechanism of NAMPT in lung fibrosis by using pharmacological inhibition on NAMPT and Nampt transgenic mice. In vivo macrophage depletion by clodronate liposomes and reinfusion of IL-4-induced M2 bone marrow-derived macrophages (BMDMs) from wild-type mice, combined with in vitro cell experiments, were performed to further validate the mechanism underlying NAMPT involving lung fibrosis. Results: We found that NAMPT increased in the lungs of patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis. NAMPT inhibitor FK866 alleviated BLM-induced pulmonary fibrosis in mice and significantly reduced NAMPT levels in bronchoalveolar lavage fluid (BALF). The lung single-cell RNA sequencing showed that NAMPT expression in monocytes/macrophages of IPF patients was much higher than in other lung cells. Knocking out NAMPT in mouse monocytes/macrophages (Namptfl/fl;Cx3cr1CreER) significantly alleviated BLM-induced pulmonary fibrosis in mice, decreased NAMPT levels in BALF, reduced the infiltration of M2 macrophages in the lungs and improved mice survival. Depleting monocytes/macrophages in Namptfl/fl;Cx3cr1CreER mice by clodronate liposomes and subsequent pulmonary reinfusion of IL-4-induced M2 BMDMs from wild-type mice, reversed the protective effect of monocyte/macrophage NAMPT-deletion on lung fibrosis. In vitro experiments confirmed that the mechanism of NAMPT engaged in pulmonary fibrosis is related to the released NAMPT by macrophages promoting M2 polarization in a non-enzyme-dependent manner by activating the STAT6 signal pathway. Conclusions: NAMPT prompts bleomycin-induced pulmonary fibrosis by driving macrophage M2 polarization in mice. Targeting the NAMPT of monocytes/macrophages is a promising strategy for treating pulmonary fibrosis.

Carbonization of quercetin into nanogels: a leap in anticoagulant development.

Quercetin, a flavonoid abundantly found in onions, fruits, and vegetables, is recognized for its pharmacological potential, especially for its anticoagulant properties that work by inhibiting thrombin and coagulation factor Xa. However, its clinical application is limited due to poor water solubility and bioavailability. To address these limitations, we engineered carbonized nanogels derived from quercetin (CNGsQur) using controlled pyrolysis and polymerization techniques. This led to substantial improvements in its anticoagulation efficacy, water solubility, and biocompatibility. We generated a range of CNGsQur by subjecting quercetin to varying pyrolytic temperatures and then assessed their anticoagulation capacities both in vitro and in vivo. Coagulation metrics, including thrombin clotting time (TCT), activated partial thromboplastin time (aPTT), and prothrombin time (PT), along with a rat tail bleeding assay, were utilized to gauge the efficacy. CNGsQur showed a pronounced extension of coagulation time compared to uncarbonized quercetin. Specifically, CNGsQur synthesized at 270 °C (CNGsQur270) exhibited the most significant enhancement in TCT, with a binding affinity to thrombin exceeding 400 times that of quercetin. Moreover, variants synthesized at 310 °C (CNGsQur310) and 290 °C (CNGsQur290) showed the most substantial delays in PT and aPTT, respectively. Our findings indicate that the degree of carbonization significantly influences the transformation of quercetin into various CNGsQur forms, each affecting distinct coagulation pathways. Additionally, both intravenous and oral administrations of CNGsQur were found to extend rat tail bleeding times by up to fivefold. Our studies also demonstrate that CNGsQur270 effectively delays and even prevents FeCl3-induced vascular occlusion in a dose-dependent manner in mice. Thus, controlled pyrolysis offers an innovative approach for generating quercetin-derived CNGs with enhanced anticoagulation properties and water solubility, revealing the potential for synthesizing self-functional carbonized nanomaterials from other flavonoids for diverse biomedical applications.