Differential impacts of nonsteroidal anti-inflammatory drugs on lifespan and healthspan in aged Caenorhabditis elegans.

Aging and age-related diseases are intricately associated with oxidative stress and inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown their promise in mitigating age-related conditions and potentially extending lifespan in various model organisms. However, the efficacy of NSAIDs in older individuals may be influenced by age-related changes in drug metabolism and tolerance, which could result in age-dependent toxicities. This study aimed to evaluate the potential risks of toxicities associated with commonly used NSAIDs (aspirin, ibuprofen, acetaminophen, and indomethacin) on lifespan, healthspan, and oxidative stress levels in both young and old Caenorhabditis elegans. The results revealed that aspirin and ibuprofen were able to extend lifespan in both young and old worms by suppressing ROS generation and enhancing the expression of antioxidant SOD genes. In contrast, acetaminophen and indomeacin accelerated aging process in old worms, leading to oxidative stress damage and reduced resistance to heat stress through the pmk-1/skn-1 pathway. Notably, the harmful effects of acetaminophen and indomeacin were mitigated when pmk-1 was knocked out in the pmk-1(km25) strain. These results underscore the potential lack of benefit from acetaminophen and indomeacin in elderly individuals due to their increased susceptibility to toxicity. Further research is essential to elucidate the underlying mechanisms driving these age-dependent responses and to evaluate the potential risks associated with NSAID use in the elderly population.

Historic dog furs unravel the origin and artificial selection of modern Nordic Lapphund and Elkhound dog breeds.

The origins and extreme morphological evolution of the modern dog breeds are poorly studied because the founder populations are extinct. Here, we analyse eight 100-200 years old dog fur samples obtained from traditional North Swedish clothing, to explore the origin and artificial selection of the modern Nordic Lapphund and Elkhound dog breeds. Population genomic analysis confirmed the Lapphund and Elkhound breeds to originate from the local dog population, and showed a distinct decrease in genetic diversity in agreement with intense breeding. We identified eleven genes under positive selection during the breed development. In particular, the MSRB3 gene, associated with breed-related ear morphology, was selected in all Lapphund and Elkhound breeds, and functional assays showed that a SNP mutation in the 3'UTR region suppresses its expression through miRNA regulation. Our findings demonstrate analysis of near-modern dog artifacts as an effective tool for interpreting the origin and artificial selection of the modern dog breeds.

The Evolution of Curve Patterns in Adolescent Idiopathic Scoliosis during Chêneau Brace Treatment.

STUDY DESIGN/SETTING: This retrospective study analyzed bracing outcomes in AIS patients, focusing on curve pattern changes and brace efficacy. OBJECTIVE: To analyze the effectiveness of the Chêneau brace across different curve patterns and to evaluate the tendencies in curve evolution during treatment. SUMMARY OF BACKGROUND DATA: Adolescent idiopathic scoliosis (AIS) presents diverse curve patterns, each responding differently to bracing. Understanding these variations is crucial for optimizing treatment strategies. METHODS: The study included 177 AIS patients treated with Chêneau orthoses, categorized based on curve patterns as per the main curve and modified Lenke (mLenke) classifications. We compared patients according to curve patterns and assessed changes in curve magnitude and pattern before and after treatment. RESULTS: Over an average follow-up of 28.1±10.7 months, the primary curve magnitude decreased from 28.8±6.6° to 25.9±10.5°. Significant reductions were observed in mLenke V and VI patients (P<0.05). Patients with main lumbar curves showed better initial in-brace correction and curve control compared with those with main thoracic curves (P<0.05). In single-curve patterns, binary logistic regression indicated that mLenke V patients demonstrated higher rates of curve control compared with mLenke I patients (P<0.05). No significant differences were found in double-curve patterns between mLenke III and VI (P>0.05). At the final follow-up, thoracolumbar/lumbar curves improved significantly in mLenke III and VI patients (P<0.05), while thoracic curves did not (P>0.05). Furthermore, at the last follow-up, the proportions of mLenke I, II, and IV increased, while mLenke III, V, and VI decreased. CONCLUSIONS: Bracing outcomes were more favorable in patients with main lumbar curves than those with main thoracic curves. However, no significant differences were found in patients with double-curve patterns. Thoracic curves exhibited a higher progression risk compared with thoracolumbar/lumbar curves within the same curve pattern. During bracing, a tendency for primary curves to shift proximally was noted.

Disease spectrum and prognostic factors in patients treated for tuberculous meningitis in Shaanxi province, China.

Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis (TB) and can be difficult to diagnose and treat. We aimed to describe the clinical presentation, diagnosis, disease spectrum, outcome, and prognostic factors of patients treated for TBM in China. Methods: A multicenter retrospective study was conducted from 2009 to 2019 enrolling all presumptive TBM patients referred to Xijing tertiary Hospital from 27 referral centers in and around Shaanxi province, China. Patients with clinical features suggestive of TBM (abnormal CSF parameters) were included in the study if they had adequate baseline information to be classified as "confirmed," "probable," or "possible" TBM according to international consensus TBM criteria and remained in follow-up. Patients with a confirmed alternative diagnosis or severe immune compromise were excluded. Clinical presentation, central nervous system imaging, cerebrospinal fluid (CSF) results, TBM score, and outcome-assessed using the modified Barthel disability index-were recorded and compared. Findings: A total of 341 presumptive TBM patients met selection criteria; 63 confirmed TBM (25 culture positive, 42 Xpert-MTB/RIF positive), 66 probable TBM, 163 possible TBM, and 49 "not TBM." Death was associated with BMRC grade III (OR = 5.172; 95%CI: 2.298-11.641), TBM score ≥ 15 (OR = 3.843; 95%CI: 1.372-10.761), age > 60 years (OR = 3.566; 95%CI: 1.022-12.442), and CSF neutrophil ratio ≥ 25% (OR = 2.298; 95%CI: 1.027-5.139). Among those with confirmed TBM, nearly one-third (17/63, 27.0%) had a TBM score < 12; these patients exhibited less classic meningitis symptoms and signs and had better outcomes compared with those with a TBM score ≥ 12. In this group, signs of disseminated/miliary TB (OR = 12.427; 95%CI: 1.138-135.758) and a higher TBM score (≥15, OR = 8.437; 95%CI: 1.328-53.585) were most strongly associated with death. Conclusion: TBM patients who are older (>60 years) have higher TBM scores or CSF neutrophil ratios, have signs of disseminated/miliary TB, and are at greatest risk of death. In general, more effort needs to be done to improve early diagnosis and treatment outcome in TBM patients.

Surgical treatment for congenital vertebral anomalies with bilateral bifid intrathoracic rib in association: A series of five cases.

Background: Congenital scoliosis is often associated with costal deformities, of which a bilateral bifid intrathoracic rib is very rare. The aim of this study was to retrospectively summarize the clinical manifestations, imaging characteristics, treatment strategies, and postoperative outcomes of five patients with bilateral bifid intrathoracic rib. Methods: We retrospectively reviewed the imaging findings and medical records of five pediatric patients (two girls, three boys) with bilateral bifid intrathoracic rib who were surgically treated for congenital kyphoscoliosis (mean age = 8 years). The clinical manifestations, imaging characteristics, treatment strategies, and postoperative outcome were summarized. Results: Four of five patients showed abnormalities from birth. All five patients presented with kyphoscoliosis and a fused vertebral body or lamina. The bilateral bifid intrathoracic rib was located at T2-3 in three patients, T7 in one patient, and T10 in one patient. Various congenital spinal deformities and multiple system malformations were present in all five patients. Three patients had preoperative neurological deficits. For corrective surgery, one patient received a traditional growing rod implantation, one patient underwent resection of a bony septum, and three patients underwent spinal osteotomy. One patient suffered complete paralysis of the lower limbs after surgery. Conclusion: Bilateral bifid intrathoracic rib is a rare anomaly that typically occurs in patients with serious kyphoscoliosis. Bilateral bifid intrathoracic rib patients show similar clinical and radiological characteristics and are likely to exhibit neurological deficits before or following corrective surgery. Spinal surgeons should be aware of the high risk of permanent neurological complications related to surgery in these patients. Level of evidence: level IV.

Association of dietary nutrient intake with type 2 diabetes: A Mendelian randomization study.

Observational research suggests that the evidence linking dietary nutrient intake (encompassing minerals, vitamins, amino acids, and unsaturated fatty acids) to type 2 diabetes (T2D) is both inconsistent and limited. This study aims to explore the potential causal relationship between dietary nutrients and T2D. Causal estimation utilized Mendelian randomization techniques. Single nucleotide polymorphisms linked to dietary nutrients were identified from existing genome-wide association studies and used as instrumental variables. Genome-wide association studies data pertinent to T2D were sourced from the DIMANTE consortium and the FinnGen database. Techniques including inverse variance weighting (IVW), weighted mode, weighted median, and Mendelian randomization-Egger were employed for causal inference, complemented by sensitivity analysis. Genetically predicted higher phenylalanine (IVW: odds ratio = 1.10 95% confidence interval 1.04-1.17, P = 1.5 × 10-3, q_pval = 3.4 × 10-2) and dihomo-gamma-linolenic acid (IVW: odds ratio = 1.001 95% confidence interval 1.0006-1.003, P = 3.7 × 10-3, q_pval = 4.1 × 10-2) levels were directly associated with T2D risk. Conversely, no causal relationships between other nutrients and T2D were established. We hypothesize that phenylalanine and dihomo-gamma-linolenic acid contribute to the pathogenesis of T2D. Clinically, the use of foods with high phenylalanine content may pose potential risks for patients with a heightened risk of T2D. Our study provides evidence supporting a causal link between dietary nutrient intake and the development of T2D.

Shexiang Tongxin Dropping Pill Promotes Angiogenesis through VEGF/eNOS Signaling Pathway on Diabetic Coronary Microcirculation Dysfunction.

OBJECTIVE: To study the effect of Shexiang Tongxin Dropping Pill (STDP) on angiogenesis in diabetic cardiomyopathy mice with coronary microcirculation dysfunction (CMD). METHODS: According to a random number table, 6 of 36 SPF male C57BL/6 mice were randomly selected as the control group, and the remaining 30 mice were injected with streptozotocin intraperitoneally to replicate the type 1 diabetes model. Mice successfully copied the diabetes model were randomly divided into the model group, STDP low-dose group [15 mg/(kg·d)], medium-dose group [30 mg/(kg·d)], high-dose group [60 mg/(kg·d)], and nicorandil group [15 mg/(kg·d)], 6 in each group. The drug was given by continuous gavage for 12 weeks. The cardiac function of mice in each group was detected at the end of the experiment, and coronary flow reserve (CFR) was detected by chest Doppler technique. Pathological changes of myocardium were observed by hematoxylin-eosin staining, collagen fiber deposition was detected by masson staining, the number of myocardial capillaries was detected by platelet endothelial cell adhesion molecule-1 staining, and the degree of myocardial hypertrophy was detected by wheat germ agglutinin staining. The expression of the vascular endothlial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) signaling pathway-related proteins in myocardial tissue was detected by Western blot. RESULTS: Compared with the model group, medium- and high-dose STDP significantly increased the left ventricular ejection fraction and left ventricular fraction shortening (P<0.01), obviously repaired the disordered cardiac muscle structure, reduced myocardial fibrosis, reduced myocardial cell area, increased capillary density, and increased CFR level (all P<0.01). Western blot showed that high-dose STDP could significantly increase the expression of VEGF and promote the phosphorylation of vascular endothelial growth factor receptor 2, phosphoinositide 3-kinase, protein kinase B, and eNOS (P<0.05 or P<0.01). CONCLUSION: STDP has a definite therapeutic effect on diabetic CMD, and its mechanism may be related to promoting angiogenesis through the VEGF/eNOS signaling pathway.

scMNMF: a novel method for single-cell multi-omics clustering based on matrix factorization.

MOTIVATION: The technology for analyzing single-cell multi-omics data has advanced rapidly and has provided comprehensive and accurate cellular information by exploring cell heterogeneity in genomics, transcriptomics, epigenomics, metabolomics and proteomics data. However, because of the high-dimensional and sparse characteristics of single-cell multi-omics data, as well as the limitations of various analysis algorithms, the clustering performance is generally poor. Matrix factorization is an unsupervised, dimensionality reduction-based method that can cluster individuals and discover related omics variables from different blocks. Here, we present a novel algorithm that performs joint dimensionality reduction learning and cell clustering analysis on single-cell multi-omics data using non-negative matrix factorization that we named scMNMF. We formulate the objective function of joint learning as a constrained optimization problem and derive the corresponding iterative formulas through alternating iterative algorithms. The major advantage of the scMNMF algorithm remains its capability to explore hidden related features among omics data. Additionally, the feature selection for dimensionality reduction and cell clustering mutually influence each other iteratively, leading to a more effective discovery of cell types. We validated the performance of the scMNMF algorithm using two simulated and five real datasets. The results show that scMNMF outperformed seven other state-of-the-art algorithms in various measurements. AVAILABILITY AND IMPLEMENTATION: scMNMF code can be found at https://github.com/yushanqiu/scMNMF.

Enhanced quantum secret sharing protocol for anonymous secure communication utilizing W states.

Quantum secret sharing (QSS) represents the fusion of quantum mechanics principles with secret information sharing, allowing a sender to distribute a secret among receivers for collective recovery. This paper introduces the concept of quantum anonymous secret sharing (QASS) to enhance the practicality of such protocols. We propose a QASS protocol leveraging W states, ensuring both recover-security and anonymity of shared secrets. Our protocol undergoes rigorous evaluation verifying their accuracy and fortifying their security against scenarios involving the active adversary. Additionally, acknowledging the imperfections inherent in real-world communication channels, we conduct a comprehensive analysis of protocol security and efficacy in noisy quantum networks. Our investigations reveal that W states exhibit good performance in mitigating noise interference, making them apt for practical applications.

Glycolytic enzyme PFKL governs lipolysis by promoting lipid droplet-mitochondria tethering to enhance ß-oxidation and tumor cell proliferation.

Lipid droplet tethering with mitochondria for fatty acid oxidation is critical for tumor cells to counteract energy stress. However, the underlying mechanism remains unclear. Here, we demonstrate that glucose deprivation induces phosphorylation of the glycolytic enzyme phosphofructokinase, liver type (PFKL), reducing its activity and favoring its interaction with perilipin 2 (PLIN2). On lipid droplets, PFKL acts as a protein kinase and phosphorylates PLIN2 to promote the binding of PLIN2 to carnitine palmitoyltransferase 1A (CPT1A). This results in the tethering of lipid droplets and mitochondria and the recruitment of adipose triglyceride lipase to the lipid droplet-mitochondria tethering regions to engage lipid mobilization. Interfering with this cascade inhibits tumor cell proliferation, promotes apoptosis and blunts liver tumor growth in male mice. These results reveal that energy stress confers a moonlight function to PFKL as a protein kinase to tether lipid droplets with mitochondria and highlight the crucial role of PFKL in the integrated regulation of glycolysis, lipid metabolism and mitochondrial oxidation.

Advancing treatment strategies for posterior malleolar malunion: The ankle dislocation method.

BACKGROUND: This study aimed to assess the radiological and clinical outcomes of treatment using the ankle dislocation method for posterior malleolar malunion. METHOD: Thirty-one patients with posterior malleolar malunion who underwent treatment using the ankle dislocation method from May 2015 to October 2021 were retrospectively analyzed. Key outcome measures were radiographic parameters (articular step-off, tibiofibular clear space, fibular length, tibial lateral surface angle, and ankle osteoarthritis), clinical scores (American Orthopaedic Foot and Ankle Society ankle-hindfoot scale and Visual Analogue Scale), and patient satisfaction rate. RESULT: Preoperative computed tomography revealed that Bartoní cek types 3 and 4 accounted for 64.5 % (n = 20) of total cases. Most posterior malleolar malunions were accompanied by depressed intercalary fragments (61.2 % [n = 19]). At the final follow-up, radiographic parameters and clinical scores showed significant improvements postoperatively (P < 0.05), with a high patient satisfaction rate of 77.4 %. Subgroup analysis revealed that the posterior malleolar fracture morphology significantly affected postoperative pain, particularly in more complex fractures (P < 0.001). CONCLUSION: The ankle dislocation method effectively exposes the distal tibial articular surface and facilitates the anatomical restoration of joint congruity under direct vision. This approach substantially improves the clinical and imaging outcomes in patients with complex posterior malleolar malunion. LEVELS OF EVIDENCE: Level IV, retrospective case series.

NEK2 contributes to radioresistance in esophageal squamous cell carcinoma by inducing protective autophagy via regulating TRIM21.

BACKGROUND: Radiotherapy (RT) has been identified as a vital treatment for esophageal squamous cell carcinoma (ESCC), while the development of radioresistance remains a major obstacle in ESCC management. The aim of this study was to investigate the effect of NIMA-related kinase 2 (NEK2) on radioresistance in ESCC cells and to reveal potential molecular mechanisms. METHODS: Human esophageal epithelial cells (HEEC) and human ESCC cell lines were obtained from the Research Center of the Fourth Hospital of Hebei Medical University (Shijiazhuang, China). Cell Counting Kit-8 (CCK-8) and flow cytometry assays were applied to assess the proliferation ability, cell cycle, apoptosis rates, and ROS production of ESCC cells. The colony-forming assay was used to estimate the effect of NEK2 on radiosensitivity. Autophagy was investigated by western blotting analysis, GFP-mRFP-LC3 fluorescence assay, and transmission electron microscopy (TEM). RESULTS: In the present study, our results showed that NEK2 was associated with radioresistance, cell cycle arrest, apoptosis, ROS production, and survival of ESCC. NEK2 knockdown could significantly inhibit growth while enhancing radiosensitivity and ROS production in ESCC cells. Interestingly, NEK2 knockdown inhibited ESCC cell autophagy and reduced autophagic flux, ultimately reversing NEK2-induced radioresistance. Mechanistically, NEK2 bound to and regulated the stability of tripartite motif-containing protein 21 (TRIM21). The accumulation of NEK2-induced light chain 3 beta 2 (LC3B II) can be reversed by the knockdown of TRIM21. CONCLUSION: These results demonstrated that NEK2 activated autophagy through TRIM21, which may provide a promising therapeutic strategy for elucidating NEK2-mediated radioresistance in ESCC.

Sulfonated Azocalix[4]arene-Modified Metal-Organic Framework Nanosheets for Doxorubicin Removal from Serum.

Chemotherapy is one of the most commonly used methods for treating cancer, but its side effects severely limit its application and impair treatment effectiveness. Removing off-target chemotherapy drugs from the serum promptly through adsorption is the most direct approach to minimize their side effects. In this study, we synthesized a series of adsorption materials to remove the chemotherapy drug doxorubicin by modifying MOF nanosheets with sulfonated azocalix[4]arenes. The strong affinity of sulfonated azocalix[4]arenes for doxorubicin results in high adsorption strength (Langmuir adsorption constant = 2.45-5.73 L mg-1) and more complete removal of the drug. The extensive external surface area of the 2D nanosheets facilitates the exposure of a large number of accessible adsorption sites, which capture DOX molecules without internal diffusion, leading to a high adsorption rate (pseudo-second-order rate constant = 0.0058-0.0065 g mg-1 min-1). These adsorbents perform effectively in physiological environments and exhibit low cytotoxicity and good hemocompatibility. These features make them suitable for removing doxorubicin from serum during "drug capture" procedures. The optimal adsorbent can remove 91% of the clinical concentration of doxorubicin within 5 min.

Evaluation of quality consistency between dispensing granules and traditional decoction of Bombyx batryticatus based on peptidomics and in silico simulations.

The application of traditional Chinese medicine dispensing granules is becoming increasingly prevalent. However, the consistency of dispensing granules with traditional decoction remains controversial. In this study, the consistency of peptide composition and pharmacodynamics between dispensing granules and traditional decoction of Bombyx batryticatus (BB) were assessed. A peptidomics method based on LC-tandem mass spectrometry technology was used to evaluate peptide composition similarity between BB traditional decoction and dispensing granules. The results revealed notable differences in peptide sequences between the two dosage forms, with only 8.55% of peptides shared between them. To evaluate the potential pharmacodynamic effects of the two dosage forms on epilepsy, virtual screening was used to identify potential active peptides, including blood-brain barrier permeability, toxicity prediction, and molecular docking. BB traditional decoction demonstrated a higher number and greater abundance of potential active peptides than BB dispensing granules, suggesting that BB traditional decoction may have a more favorable effect in treating epilepsy compared with BB dispensing granules. Moreover, molecular docking and molecular dynamics simulation studies confirmed the mechanism of action of active peptides to γ-aminobutyric acid transporter 1 (GAT-1). This study provides a scientific basis for the evaluation of quality consistency between BB traditional decoction and dispensing granules.

Precise lymph node biopsy for endometrial cancer confined to the uterus: Analysis of 43 clinical cases.

OBJECTIVE: To explore a precise association between tumor location and lymph node (LN) biopsy algorithm in uterine confined endometrial cancer (EC). MATERIALS AND METHODS: Patients with EC treated in the Department of Obstetrics and Gynecology, South Branch of Fujian Provincial Hospital were included in this observational retrospective study. Based on the procedure of treatment, patients were separated to stage I (2015.07-2019.09) and stage II (2019.09-2021.9). In each stage, patients were separated to high and low-risk group by the predicted results. Patients in the high-risk group received systematic lymphadenectomy in stage I and sentinel lymph node (SLN) dissection in stage II. The efficiency of lymph node metastasis (LNM) detection rates was compared between stage I and stage II cases. Precise lymph node biopsy algorithm was also constructed based on the outcomes of stage II. RESULTS: Overall, 43 patients, 28 in stage I and 15 in stage II, were included in the study. No recurrence or death cases had been found within follow-up terms. Based on the difference in the detection efficiency of LNM (p > 0.05), there was no difference between two stages. Thus, systematic lymphadenectomy and SLN biopsy provided similar success rates. The location of tumor site was also important for deciding whether pelvic or para-aortic SLN should be sampled for LNM. CONCLUSIONS: Precise SLN biopsy for EC confined to the uterus showed comparable LNM detection rate as systematic lymphadenectomy. EC location may be used to determine whether pelvic or para-aortic SLN sampling should be conducted for treatment.

LncRNAs as nodes for the cross-talk between autophagy and Wnt signaling in pancreatic cancer drug resistance.

Pancreatic cancer is a malignancy with high mortality. In addition to the few symptoms until the disease reaches an advanced stage, the high fatality rate is attributed to its rapid development, drug resistance and lack of appropriate treatment. In the selection and research of therapeutic drugs, gemcitabine is the first-line drug for pancreatic cancer. Solving the problem of gemcitabine resistance in pancreatic cancer will contribute to the progress of pancreatic cancer treatment. Long non coding RNAs (lncRNAs), which are RNA transcripts longer than 200 nucleotides, play vital roles in cellular physiological metabolic activities. Currently, our group and others have found that some lncRNAs are aberrantly expressed in pancreatic cancer cells, which can regulate the process of cancer through autophagy and Wnt/ß-catenin pathways simultaneously and affect the sensitivity of cancer cells to therapeutic drugs. This review presents an overview of the recent evidence concerning the node of lncRNA for the cross-talk between autophagy and Wnt/ß-catenin signaling in pancreatic cancer, together with the practicability of lncRNAs and the core regulatory factors as targets in therapeutic resistance.

Supramolecular 3 in 1: A Lubrication and Co-Delivery System for Synergistic Advanced Osteoarthritis Therapy.

The complexity, heterogeneity, and drug resistance of diseases necessitate a shift in therapeutic paradigms from monotherapy to combination therapy, which could augment treatment efficiency. Effective treatment of advanced osteoarthritis (OA) requires addressing three key factors contributing to its deterioration: chronic joint inflammation, lubrication dysfunction, and cartilage-tissue degradation. Herein, we present a supramolecular nanomedicine of multifunctionality via molecular recognition and self-assembly. The employed macrocyclic carrier, zwitterion-modified cavitand (CV-2), not only accurately loads various drugs but also functions as a therapeutic agent with lubricating properties for the treatment of OA. Kartogenin (KGN), a drug for articular cartilage regeneration and protection, and flurbiprofen (FP), an anti-inflammatory agent, were coloaded onto CV-2 assembly, forming a supramolecular nanomedicine KGN&FP@CV-2. The three-in-one combination therapy of KGN&FP@CV-2 addresses the three pathological features for treating OA collectively, and thus provides long-term therapeutic benefits for OA through sustained drug release and intrinsic lubrication in vivo. The multifunctional integration of macrocyclic delivery and therapeutics provides a simple, flexible, and universal platform for the synergistic treatment of diseases involving multiple drugs.

Supramolecular interaction in the action of drug delivery systems.

Complex diseases and diverse clinical needs necessitate drug delivery systems (DDSs), yet the current performance of DDSs is far from ideal. Supramolecular interactions play a pivotal role in various aspects of drug delivery, encompassing biocompatibility, drug loading, stability, crossing biological barriers, targeting, and controlled release. Nevertheless, despite having some understanding of the role of supramolecular interactions in drug delivery, their incorporation is frequently overlooked in the design and development of DDSs. This perspective provides a brief analysis of the involved supramolecular interactions in the action of drug delivery, with a primary emphasis on the DDSs employed in the clinic, mainly liposomes and polymers, and recognized phenomena in research, such as the protein corona. The supramolecular interactions implicated in various aspects of drug delivery systems, including biocompatibility, drug loading, stability, spatiotemporal distribution, and controlled release, were individually analyzed and discussed. This perspective aims to trigger a comprehensive and systematic consideration of supramolecular interactions in the further development of DDSs. Supramolecular interactions embody the true essence of the interplay between the majority of DDSs and biological systems.

Functional and structural dissection of glycosyltransferases underlying the glycodiversity of wolfberry-derived bioactive ingredients lycibarbarspermidines.

Lycibarbarspermidines are unusual phenolamide glycosides characterized by a dicaffeoylspermidine core with multiple glycosyl substitutions, and serve as a major class of bioactive ingredients in the wolfberry. So far, little is known about the enzymatic basis of the glycosylation of phenolamides including dicaffeoylspermidine. Here, we identify five lycibarbarspermidine glycosyltransferases, LbUGT1-5, which are the first phenolamide-type glycosyltransferases and catalyze regioselective glycosylation of dicaffeoylspermidines to form structurally diverse lycibarbarspermidines in wolfberry. Notably, LbUGT3 acts as a distinctive enzyme that catalyzes a tandem sugar transfer to the ortho-dihydroxy group on the caffeoyl moiety to form the unusual ortho-diglucosylated product, while LbUGT1 accurately discriminates caffeoyl and dihydrocaffeoyl groups to catalyze a site-selective sugar transfer. Crystal structure analysis of the complexes of LbUGT1 and LbUGT3 with UDP, combined with molecular dynamics simulations, revealed the structural basis of the difference in glycosylation selectivity between LbUGT1 and LbUGT3. Site-directed mutagenesis illuminates a conserved tyrosine residue (Y389 in LbUGT1 and Y390 in LbUGT3) in PSPG box that plays a crucial role in regulating the regioselectivity of LbUGT1 and LbUGT3. Our study thus sheds light on the enzymatic underpinnings of the chemical diversity of lycibarbarspermidines in wolfberry, and expands the repertoire of glycosyltransferases in nature.