Drug-induced liver injury in children: A nationwide cohort study from China.

Background & Aims: Currently, there is limited knowledge on the clinical profile of drug-induced liver injury (DILI) in Chinese children. We aimed to assess the clinical characteristics, suspected drugs, and outcomes associated with pediatric DILI in China. Methods: This nationwide, multicenter, retrospective study, conducted between 2012 and 2014, analyzed 25,927 cases of suspected DILI at 308 medical centers using the inpatient medical register system. Utilizing the Roussel Uclaf causality assessment method score, only patients with scores ≥6 or diagnosed with DILI by three experts after scoring <6 were included in the analysis. Among them, 460 cases met the EASL biochemical criteria. The study categorized children into three age groups: toddlers (≥30 days to <6 years old), school-age children (6 to <12 years old), and adolescents (12 to <18 years old). Results: Hepatocellular injury was the predominant clinical classification, accounting for 63% of cases, with 34% of these cases meeting Hy's law criteria. Adolescents comprised the majority of children with moderate/severe DILI (65%). Similarly, adolescents faced a significantly higher risk of severe liver injury compared to younger children (adjusted odd ratios 4.75, p = 0.002). The top three most frequently prescribed drug classes across all age groups were antineoplastic agents (25.9%), antimicrobials (21.5%), and traditional Chinese medicine (13.7%). For adolescents, the most commonly suspected drugs were antitubercular drugs (22%) and traditional Chinese medicine (23%). Conclusion: Adolescents are at a greater risk of severe and potentially fatal liver injury compared to younger children. Recognizing the risk of pediatric DILI is crucial for ensuring safe medical practices. Impact and implications: Drug-induced liver injury, a poorly understood yet serious cause of pediatric liver disease, encompasses a spectrum of clinical presentations, ranging from asymptomatic liver enzyme elevation to acute liver failure. This retrospective study, utilizing a large Chinese cohort of pediatric liver injury cases from 308 centers nationwide, characterized the major clinical patterns and suspected drugs in detail, revealing that adolescents are at a greater risk of severe liver injury compared to younger children. Vigilant care and careful surveillance of at-risk pediatric patients are crucial for physicians, researchers, patients, caregivers, and policymakers. Additional multicenter prospective studies are needed to evaluate the risk of hepatotoxicity in outpatients and hospitalized pediatric patients.

Advances in tumor stroma-based targeted delivery.

The tumor stroma plays a crucial role in tumor progression, and the interactions between the extracellular matrix, tumor cells, and stromal cells collectively influence tumor progression and the efficacy of therapeutic agents. Currently, utilizing components of the tumor stroma for drug delivery is a noteworthy strategy. A number of targeted drug delivery systems designed based on tumor stromal components are entering clinical trials. Therefore, this paper provides a thorough examination of the function of tumor stroma in the advancement of targeted drug delivery systems. One approach is to use tumor stromal components for targeted drug delivery, which includes certain stromal components possessing inherent targeting capabilities like HA, laminin, along with targeting stromal cells homologously. Another method entails directly focusing on tumor stromal components to reshape the tumor stroma and facilitate drug delivery. These drug delivery systems exhibit great potential in more effective cancer therapy strategies, such as precise targeting, enhanced penetration, improved safety profile, and biocompatibility. Ultimately, the deployment of these drug delivery systems can deepen our comprehension of tumor stroma and the advanced development of corresponding drug delivery systems.

Cellular senescence in metastatic prostate cancer: A therapeutic opportunity or challenge (Review).

The treatment of patients with metastatic prostate cancer (PCa) is considered to be a long­standing challenge. Conventional treatments for metastatic PCa, such as radical prostatectomy, radiotherapy and androgen receptor­targeted therapy, induce senescence of PCa cells to a certain extent. While senescent cells can impede tumor growth through the restriction of cell proliferation and increasing immune clearance, the senescent microenvironment may concurrently stimulate the secretion of a senescence­associated secretory phenotype and diminish immune cell function, which promotes PCa recurrence and metastasis. Resistance to established therapies is the primary obstacle in treating metastatic PCa as it can lead to progression towards an incurable state of disease. Therefore, understanding the molecular mechanisms that underly the progression of PCa is crucial for the development of novel therapeutic approaches. The present study reviews the phenomenon of treatment­induced senescence in PCa, the dual role of senescence in PCa treatments and the mechanisms through which senescence promotes PCa metastasis. Furthermore, the present review discusses potential therapeutic strategies to target the aforementioned processes with the aim of providing insights into the evolving therapeutic landscape for the treatment of metastatic PCa.

Risk factors for cement leakage after percutaneous vertebral augmentation for osteoporotic vertebral compression fractures: a meta-analysis.

BACKGROUND: Osteoporotic vertebral compression fractures (OVCF) may necessitate percutaneous vertebral augmentation (PVA), a procedure not without its risks. One notable complication is cement leakage (CL), which can cause significant distress in patients. Despite its clinical importance, there remains a paucity of meta-analyses investigating these complications and their management in the existing literature. MATERIAL AND METHODS: We systematically reviewed PubMed, Cochrane Library, Embase, and Web of Science databases up to February 2024 to identify studies examining CL following PVA treatment in OVCF. We assessed the quality of eligible cohort studies using the Newcastle-Ottawa Scale (NOS), extracted data on incidence, identified risk factors for CL, and conducting meta-analysis with Revman 5.2 software. We calculated odd ratios (OR) and Mean Differences (MD) with 95% confidence interval (CI) applying random effects models. RESULTS: We identified twelve cohort studies that matched our strict inclusion criteria. These studies included a total of 2388 patients and 3392 vertebrae. CL was identified in 1132 vertebrae. Notable risk factors for CL included compromised cortical bone integrity (OR 5.00, 95% CI 3.01~8.29, P<0.00001), presence of intravertebral vacuum clefts (OR 1.68, 95% CI 1.07~2.65, P=0.03), basivertebral foramen sign (OR 1.77, 95% CI 1.09~2.89, P=0.02), and volume of cement used (MD 0.75, 95% CI 0.41~1.10, P<0.0001). CONCLUSION: Our findings underscore the significance of cortical bone integrity, intravertebral vacuum cleft, basivertebral foramen sign, and cement volume as principal determinants of CL risk in PVA for OVCF. These insights advocate for tailored surgical strategies to mitigate the risk of CL in this patient population.

Ruthenium Complexes with NNN-Pincer Ligands for N-Methylation of Amines Using Methanol.

A series of ruthenium complexes (Ru1-Ru4) bearing new NNN-pincer ligands were synthesized in 58-78% yields. All of the complexes are air and moisture stable and were characterized by IR, NMR, and high-resolution mass spectra (HRMS). In addition, the structures of Ru1-Ru3 were confirmed by X-ray crystallographic analysis. These Ru(II) complexes exhibited high catalytic efficiency and broad functional group tolerance in the N-methylation reaction of amines using CH3OH as both the C1 source and solvent. Experimental results indicated that the electronic effect of the substituents on the ligands considerably affects the catalytic reactivity of the complexes in which Ru3 bearing an electron-donating OMe group showed the highest activity. Deuterium labeling and control experiments suggested that the dehydrogenation of methanol to generate ruthenium hydride species was the rate-determining step in the reaction. Furthermore, this protocol also provided a ready approach to versatile trideuterated N-methylamines under mild conditions using CD3OD as a deuterated methylating agent.

[Percutaneous pedicle screw anchored vertebral augmentation for the treatment of Kümmell disease without neurological symptoms].

OBJECTIVE: To explore the clinical effect of percutaneous pedicle screw anchored vertebral augmentation(PPSAVA) in the treatment of asymptomatic Kümmell disease without neurological symptoms. METHODS: The clinical data of 20 patients with Kümmell disease without neurological symptoms treated with PPSAVA in our hospital from January 2019 to December 2021 were analyzed retrospectively, including 5 males and 15 females, aged 56 to 88 (74.95±9.93) years old. and the course of disease was 7 to 60 days with an average of (21.35±14.46) days. All patients were treated with PPSAVA. The time of operation, the amount of bone cement injected and the leakage of bone cement were recorded. The visual analogue scale(VAS), Oswestry disability index(ODI), vertebral body angle(VBA), anterior edge height and midline height of vertebral body were compared among the before operation, 3 days after operation and during the final follow-up. The loosening and displacement of bone cement were observed during the final follow-up. RESULTS: All the 20 patients completed the operation successfully. The operation time was 30 to 56 min with an average of (41.15±7.65) min, and the amount of bone cement injection was 6.0 to 12.0 ml with an average of (9.30±1.49) ml. Bone cement leakage occurred in 6 cases and there were no obvious clinical symptoms. The follow-up time was 6 to 12 months with an average of (8.43±2.82) months. The VBA, anterior edge height and midline height of of injured vertebral body were significantly improved 3 days after operation and the final follow-up(P<0.05), and the VBA, anterior edge height and midline height of of injured vertebral body were lost in different degrees at the final follow-up (P<0.05). The VAS and ODI at 3 days after operation and at the final follow-up were significantly lower than those at preoperatively(P<0.05), but the VAS score and ODI at the final follow-up were not significantly different from those at 3 d after operation(P>0.05). At the last follow-up, no patients showed loosening or displacement of bone cement. CONCLUSION: PPSAVA is highly effective in treating Kümmell disease without neurological symptoms, improving patients' pain and functional impairment, and reducing the risk of cement loosening and displacement postoperatively.

The mean Hounsfield unit range acquired from different slices produces superior predictive accuracy for pyonephrosis in obstructive uropathy.

PURPOSE: To determine the non-contrast computer tomography imaging features of pyonephrosis and evaluate the predictive value of Hounsfield units (HUs) in different hydronephrotic region slices. MATERIALS AND METHODS: We retrospectively reviewed data from patients with hydronephrosis who had renal-ureteral calculi. All patients were categorized into pyonephrosis and simple hydronephrosis groups. Baseline characteristics, the mean HU values in the maximal hydronephrotic region (uHU) slice, and the range of uHU in different slices (ΔuHU) were compared between the two groups. Univariate and multivariate analyses were performed to identify risk factors for pyonephrosis. RESULTS: Among the 181 patients enrolled in the current study, 71 patients (39.2%) were diagnosed with pyonephrosis. The mean dilated pelvis surface areas were comparable between patients with pyonephrosis and simple hydronephrosis (822.61 mm² vs. 877.23 mm², p=0.722). Collecting system debris (p=0.022), a higher uHU (p=0.038), and a higher ΔuHU (p<0.001) were identified as independent risk factors for pyonephrosis based on multivariate analysis. The ΔuHU sensitivity and specificity were 88.7% and 86.4%, respectively, at a cutoff value of 6.56 (p<0.001), whereas the sensitivity and specificity for detecting pyonephrosis at a uHU cutoff value of 7.96 was 50.7% and 70.9%, respectively (p=0.003). CONCLUSIONS: Non-contrast computer tomography was shown to accurately distinguish simple hydronephrosis from pyonephrosis in patients with obstructive uropathy. Evaluation of the ΔuHU in different slices may be more reliable than the uHU acquired from a single slice in predicting pyonephrosis.

Effectiveness of a broad-spectrum bivalent mRNA vaccine against SARS-CoV-2 variants in preclinical studies.

Vaccines utilizing modified messenger RNA (mRNA) technology have shown robust protective efficacy against SARS-CoV-2 in humans. As the virus continues to evolve in both human and non-human hosts, risk remains that the performance of the vaccines can be compromised by new variants with strong immune escape abilities. Here we present preclinical characterizations of a novel bivalent mRNA vaccine RQ3025 for its safety and effectiveness in animal models. The mRNA sequence of the vaccine is designed to incorporate common mutations on the SARS-CoV-2 spike protein that have been discovered along the evolutionary paths of different variants. Broad-spectrum, high-titer neutralizing antibodies against multiple variants were induced in mice (BALB/c and K18-hACE2), hamsters and rats upon injections of RQ3025, demonstrating advantages over the monovalent mRNA vaccines. Effectiveness in protection against several newly emerged variants is also evident in RQ3025-vaccinated rats. Analysis of splenocytes derived cytokines in BALB/c mice suggested that a Th1-biased cellular immune response was induced by RQ3025. Histological analysis of multiple organs in rats following injection of a high dose of RQ3025 showed no evidence of pathological changes. This study proves the safety and effectiveness of RQ3025 as a broad-spectrum vaccine against SARS-CoV-2 variants in animal models and lays the foundation for its potential clinical application in the future.

Combination effect of Chinese kidney-tonifying granules and platelet-rich plasma gels on enhancing bone healing in rat models with femur defects.

BACKGROUND: The traditional Chinese kidney-tonifying granules, known as Bushen Zhongyao Keli (BSZYKL), have been found to stimulate calcium salt deposition, enhance bone formation, and foster bone growth within the bone matrix at sites of bone defects. On the other hand, platelet-rich plasma (PRP) is enriched with various growth factors capable of facilitating the repair of bone defects and enhancing bone strength following fractures. This study is dedicated to investigating the combined efficacy of BSZYKL and PRP gel (PRP-G) in the treatment of bone defects. METHODS: We established a femur defect model in male Sprague-Dawley (SD) rats and filled the defect areas with autologous coccygeal bone and PRP-G. For 8 consecutive weeks, those rats were given with intragastric administration of BSZYKL. Biomechanical characteristics of the femur were assessed 28 days after intramuscular administration. On day 56, bone formation was examined using X-ray, micro-CT, and transmission electron microscopy. Additionally, we analyzed the expression of bone formation markers, Runx2 and Osterix, in femur tissues through qPCR, Western blotting, and immunohistochemistry. RESULTS: Rats receiving the combined treatment of BSZYKL and PRP-G exhibited drastically enhanced femoral peak torsion, failure angle, energy absorption capacity, and torsional stiffness as compared to control group. This combination therapy also led to marked improvements in bone volume, mass, and microarchitecture, accompanied by elevated expressions of Runx2 and Osterix when compared to control group. Notably, the synergistic effects of BSZYKL and PRP-G in treating bone defects surpassed the effects of either treatment alone. CONCLUSIONS: These findings revealed the potential of BSZYKL in combination with PRP-G in improving bone defects.

Copper Complexes with N,N,N-Tridentate Quinolinyl Anilido-Imine Ligands: Synthesis and Their Catalytic Application in Chan-Lam Reactions.

The treatment of 2-(ArNC(H))C6H4-HNC9H6N with n-BuLi and the subsequent addition of CuCl2 afforded the anilido-aldimine Cu(II) complexes 1-5 Cu[{2-[ArN=C(H)]C6H4}N(8-C9H6N)]Cl (Ar = 2,6-iPr2C6H3 (1), 2,4,6-(CH3)3C6H2 (2), 4-OCH3C6H4 (3), 4-BrC6H4 (4), 4-ClC6H4 (5)), respectively. All the copper complexes were fully characterized by IR, EPR and HR-MS spectra. The X-ray diffraction analysis reveals that 2 and 4 are mononuclear complexes, and the Cu atom is sitting in a slightly square-planar geometry. These Cu(II) complexes have exhibited excellent catalytic activity in the Chan-Lam coupling reactions of benzimidazole derivatives with arylboronic acids, achieving the highest yields of up to 96%.

Preclinical evaluation of RQ3013, a broad-spectrum mRNA vaccine against SARS-CoV-2 variants.

The global emergence of SARS-CoV-2 variants has led to increasing breakthrough infections in vaccinated populations, calling for an urgent need to develop more effective and broad-spectrum vaccines to combat COVID-19. Here we report the preclinical development of RQ3013, an mRNA vaccine candidate intended to bring broad protection against SARS-CoV-2 variants of concern (VOCs). RQ3013, which contains pseudouridine-modified mRNAs formulated in lipid nanoparticles, encodes the spike (S) protein harboring a combination of mutations responsible for immune evasion of VOCs. Here we characterized the expressed S immunogen and evaluated the immunogenicity, efficacy, and safety of RQ3013 in various animal models. RQ3013 elicited robust immune responses in mice, hamsters, and nonhuman primates (NHP). It can induce high titers of antibodies with broad cross-neutralizing ability against the wild-type, B.1.1.7, B.1.351, B.1.617.2, and the newly emerging Omicron variants. In mice and NHP, two doses of RQ3013 protected the upper and lower respiratory tract against infection by SARS-CoV-2 and its variants. Furthermore, our safety assessment of RQ3013 in NHP showed no observable adverse effects. These results provide strong support for the evaluation of RQ3013 in clinical trials and suggest that it may be a promising candidate for broad protection against COVID-19 and its variants.

Surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy of rectal adenocarcinoma with penile metastasis: a case report.

Background: Despite the rich proximity and vascularization to the pelvic organs, metastatic lesions to the penis are incredibly uncommon. Most primary tumors are genitourinary cancers, and rectal origins are rare. Only 56 cases of metastatic penile tumors have been reported since 1870. Several palliative or curative methods, such as chemotherapy, total penectomy, and radiotherapy, have been applied to treat this condition in previous cases; however, the patient prognosis is poor. Immunotherapy is a beneficial treatment approach for multiple cancers, and recent investigations have shown that it may be beneficial for patients with advanced penile cancer. Case Description: Herein, we report the case of a 59-year-old Chinese man who had metastatic adenocarcinoma in the penile tissue 3 years after rectal cancer resection. The patient presented with penile pain and dysuria for 6 months when he was 54 years old, and Immunohistochemical staining showed that the origin was the rectum after total penectomy. The patient received surgery, chemotherapy, radiotherapy, targeted therapy and immunotherapy positively and still survived for a further 4 years and 6 months following penectomy despite the late metastasis of rectal cancer. There are two major changes and progress after penectomy, all of which have undergone surgical treatment during continuous treatment and follow-up, the patient completed right inguinal lymphadenectomy when his right regional nodes metastasis was found 23 months after penectomy. While the patient suffered from radiation injury after 47 months after penectomy, which led to radiation necrosis and hip soft tissue infection, and the patient tended to lay prone instead of lying on the back because of the hip pain. The patient ultimately died of multiple organ failure. Conclusions: All of the previously reported cases of penile metastasis from rectal cancer since 1870 have been reviewed. Yet, the metastatic prognosis remains poor regardless of the treatment options, except for lesions where metastasis is only limited to the penis. We found that the patient may derive more benefit from strategic therapies including surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy.

Unusual substructure conformations observed in crystal structures of a dicistrovirus RNA-dependent RNA polymerase suggest contribution of the N-terminal extension in proper folding.

The Dicistroviridae is a virus family that includes many insect pathogens. These viruses contain a positive-sense RNA genome that is replicated by the virally encoded RNA-dependent RNA polymerase (RdRP) also named 3Dpol. Compared with the Picornaviridae RdRPs such as poliovirus (PV) 3Dpol, the Dicistroviridae representative Israeli acute paralysis virus (IAPV) 3Dpol has an additional N-terminal extension (NE) region that is about 40-residue in length. To date, both the structure and catalytic mechanism of the Dicistroviridae RdRP have remain elusive. Here we reported crystal structures of two truncated forms of IAPV 3Dpol, namely Δ85 and Δ40, both missing the NE region, and the 3Dpol protein in these structures exhibited three conformational states. The palm and thumb domains of these IAPV 3Dpol structures are largely consistent with those of the PV 3Dpol structures. However, in all structures, the RdRP fingers domain is partially disordered, while different conformations of RdRP substructures and interactions between them are also present. In particular, a large-scale conformational change occurred in the motif B-middle finger region in one protein chain of the Δ40 structure, while a previously documented alternative conformation of motif A was observed in all IAPV structures. These experimental data on one hand show intrinsic conformational variances of RdRP substructures, and on the other hand suggest possible contribution of the NE region in proper RdRP folding in IAPV.

Structural basis of a two-step tRNA recognition mechanism for plastid glycyl-tRNA synthetase.

Two types of glycyl-tRNA synthetase (GlyRS) are known, the α2 and the α2ß2 GlyRSs. Both types of synthetase employ a class II catalytic domain to aminoacylate tRNAGly. In plastids and some bacteria, the α and ß subunits are fused and are designated as (αß)2 GlyRSs. While the tRNA recognition and aminoacylation mechanisms are well understood for α2 GlyRSs, little is known about the mechanisms for α2ß2/(αß)2 GlyRSs. Here we describe structures of the (αß)2 GlyRS from Oryza sativa chloroplast by itself and in complex with cognate tRNAGly. The set of structures reveals that the U-shaped ß half of the synthetase selects the tRNA in a two-step manner. In the first step, the synthetase engages the elbow and the anticodon base C35 of the tRNA. In the second step, the tRNA has rotated ∼9° toward the catalytic centre. The synthetase probes the tRNA for the presence of anticodon base C36 and discriminator base C73. This intricate mechanism enables the tRNA to access the active site of the synthetase from a direction opposite to that of most other class II synthetases.

Single-cell transcriptomic analysis of tumor heterogeneity and intercellular networks in human urothelial carcinoma.

BACKGROUND: Heterogeneity of tumor cells and the tumor microenvironment (TME) is significantly associated with clinical outcomes and treatment responses in patients with urothelial carcinoma (UC). Comprehensive profiling of the cellular diversity and interactions between malignant cells and TME may clarify the mechanisms underlying UC progression and guide the development of novel therapies. This study aimed to extend our understanding of intra-tumoral heterogeneity and the immunosuppressive TME in UC and provide basic support for the development of novel UC therapies. METHODS: Seven patients with UC were included who underwent curative surgery at our hospital between July 2020 and October 2020. We performed single-cell RNA sequencing (scRNA-seq) analysis in seven tumors with six matched adjacent normal tissues and integrated the results with two public scRNA-seq datasets. The functional properties and intercellular interactions between single cells were characterized, and the results were validated using multiplex immunofluorescence staining, flow cytometry, and bulk transcriptomic datasets. All statistical analyses were performed using the R package with two-sided tests. Wilcoxon-rank test, log-rank test, one-way analysis of variance test, and Pearson correlation analysis were used properly. RESULTS: Unsupervised t-distributed stochastic neighbor embedding clustering analysis identified ten main cellular subclusters in urothelial tissues. Of them, seven urothelial subtypes were noted, and malignant urothelial cells were characterized with enhanced cellular proliferation and reduced immunogenicity. CD8 + T cell subclusters exhibited enhanced cellular cytotoxicity activities along with increased exhaustion signature in UC tissues, and the recruitment of CD4 + T regulatory cells was also increased in tumor tissues. Regarding myeloid cells, coordinated reprogramming of infiltrated neutrophils, M2-type polarized macrophages, and LAMP3 + dendritic cells contribute to immunosuppressive TME in UC tissues. Tumor tissues demonstrated enhanced angiogenesis mediated by KDR + endothelial cells and RGS5 + /ACTA2 + pericytes. Through deconvolution analysis, we identified multiple cellular subtypes may influence the programmed death-ligand 1 (PD-L1) immunotherapy response in patients with UC. CONCLUSION: Our scRNA-seq analysis clarified intra-tumoral heterogeneity and delineated the pro-tumoral and immunosuppressive microenvironment in UC tissues, which may provide novel therapeutic targets.

Comprehensive structural characterization of the human AAA+ disaggregase CLPB in the apo- and substrate-bound states reveals a unique mode of action driven by oligomerization.

The human AAA+ ATPase CLPB (SKD3) is a protein disaggregase in the mitochondrial intermembrane space (IMS) and functions to promote the solubilization of various mitochondrial proteins. Loss-of-function CLPB mutations are associated with a few human diseases with neutropenia and neurological disorders. Unlike canonical AAA+ proteins, CLPB contains a unique ankyrin repeat domain (ANK) at its N-terminus. How CLPB functions as a disaggregase and the role of its ANK domain are currently unclear. Herein, we report a comprehensive structural characterization of human CLPB in both the apo- and substrate-bound states. CLPB assembles into homo-tetradecamers in apo-state and is remodeled into homo-dodecamers upon substrate binding. Conserved pore-loops (PLs) on the ATPase domains form a spiral staircase to grip and translocate the substrate in a step-size of 2 amino acid residues. The ANK domain is not only responsible for maintaining the higher-order assembly but also essential for the disaggregase activity. Interactome analysis suggests that the ANK domain may directly interact with a variety of mitochondrial substrates. These results reveal unique properties of CLPB as a general disaggregase in mitochondria and highlight its potential as a target for the treatment of various mitochondria-related diseases.

Nitric Oxide-Loaded Bioinspired Lipoprotein Normalizes Tumor Vessels To Improve Intratumor Delivery and Chemotherapy of Albumin-Bound Paclitaxel Nanoparticles.

The disorganized vasculatures in tumors represent a substantial challenge of intratumor nanomedicine delivery to exert the anticancer effects. Herein, we rationally designed a glutathione (GSH)-activated nitric oxide (NO) donor loaded bioinspired lipoprotein system (NO-BLP) to normalize tumor vessels and then promote the delivery efficiency of sequential albumin-bound paclitaxel nanoparticles (PAN) in tumors. NO-BLP exhibited higher tumor accumulation and deeper penetration versus the counterpart liposomal formulation (NO-Lipo) in 4T1 breast cancer tumors, thus producing notable vascular normalization efficacy and causing a 2.33-fold increase of PAN accumulation. The sequential strategy of NO-BLP plus PAN resulted in an 81.03% inhibition of tumor growth in 4T1 tumors, which was better than the NO-BLP monotherapy, PAN monotherapy, and the counterpart NO-Lipo plus PAN treatment. Therefore, the bioinspired lipoprotein of NO-BLP provides an encouraging platform to normalize tumor vessels and promote intratumor delivery of nanomedicines for effective cancer treatment.

Structural basis of transition from initiation to elongation in de novo viral RNA-dependent RNA polymerases.

De novo viral RNA-dependent RNA polymerases (RdRPs) utilize their priming element (PE) to facilitate accurate initiation. Upon transition to elongation, the PE has to retreat from the active site to give room to the template-product RNA duplex. However, PE conformational change upon this transition and the role of PE at elongation both remain elusive. Here, we report crystal structures of RdRP elongation complex (EC) from dengue virus serotype 2 (DENV2), demonstrating a dramatic refolding of PE that allows establishment of interactions with the RNA duplex backbone approved to be essential for EC stability. Enzymology data from both DENV2 and hepatitis C virus (HCV) RdRPs suggest that critical transition of the refolding likely occurs after synthesis of a 4- to 5-nucleotide (nt) product together providing a key basis in understanding viral RdRP transition from initiation to elongation.

Full factorial design, physicochemical characterization, ex vivo investigation, and biological assessment of glutathione-loaded solid lipid nanoparticles for topical application.

l-Glutathione (GSH) has exceptional antioxidant activities against UVA irradiation-induced oxidative stress and is used widely for combatting skin ageing. However, topical administration of GSH is challenging due to its inability to penetrate the stratum corneum (SC). This study aims to evaluate the solid lipid nanoparticles (SLNs) carrier system for improving the skin penetration and stability of GSH. The GSH-loaded SLNs (GSH-SLNs) were prepared by the double emulsion technique and were optimized by a full factorial design. The optimized GSH-SLNs formulation had a mean particle size of 305 ± 0.6 nm and a zeta potential of + 20.1 ± 9.5 mV, suitable for topical delivery. The ex-vivo penetration study using human skin demonstrated a 3.7-fold improvement of GSH penetration across SC with GSH-SLNs when compared with aqueous GSH. GSH-SLNs prolonged antioxidant activity on UVA irradiated fibroblast cells when compared to GSH solution, preventing UVA-induced cell death and promoting cell growth for times over 48 h. This research has illustrated that as a carrier system, SLNs were able to enhance the physicochemical stability, skin penetration, and drug deposition in the viable epidermis and dermis layers of the skin for GSH, while also maintaining the ability to protect human skin fibroblast cells against oxidative stress caused by UVA irradiation. This delivery system shows future promise as a topical delivery platform for the topical delivery of GSH and other chemically similar bioactive compounds for improving skin health.