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L‐type amino acid transporter 1 (LAT1), overexpressed on the membrane of various tumor cells, is a potential target for tumor‐targeting therapy. This study aimed to develop a LAT1‐mediated chemotherapeutic agent. We screened doxorubicin modified by seven different large neutral amino acids. The aspartate‐modified doxorubicin (Asp‐DOX) showed the highest affinity (Km = 41.423 μmol/L) to LAT1. Aspartate was attached to the N‐terminal of DOX by the amide bond with a free carboxyl and a free amino group on the α‐carbon atom of the Asp residue. The product Asp‐DOX was characterized by HPLC/MS. In vitro, Asp‐DOX exerted stronger inhibition on the cancer cells overexpressing LAT1 and the uptake of Asp‐DOX was approximately 3.5‐fold higher than that of DOX in HepG2 cells. Pharmacokinetic data also showed that Asp‐DOX was expressed over a longer circulation time (t1/2 = 49.14 min) in the blood compared to DOX alone (t1/2 = 15.12 min). In HepG2 and HCT116 tumor‐bearing mice, Asp‐DOX achieved 3.1‐fold and 6.4‐fold accumulation of drugs in tumor tissue, respectively, than those of the unmodified DOX. More importantly, treatment of tumor‐bearing mice with Asp‐DOX showed a significantly stronger inhibition of tumor growth than mice treated with free DOX in HepG2 tumor models. Furthermore, after Asp modification, Asp‐DOX avoided MDR mediated by P‐glycoprotein. These results suggested that the Asp‐DOX modified drug may provide a new treatment strategy for tumors that overexpress LAT1 and MDR1. In this paper, we screened one compound Asp‐DOX from others targeting to LAT1. Asp‐DOX showed a stong selective cytotoxicty to the cancer cells overexpressed LAT1 in vitro and in vivo. What's more, Asp‐DOX successfully avioded the resistance of cancer cells induced by MDR1 and this was the first report about targeting therapy on LAT1 transporter.

Objective Renal function can modify the outcomes of large vessel occlusion (LVO) stroke across stroke etiologies in disparate degrees. The presence of renal function deficit can also impair the pharmacokinetics of tirofiban. Hence, this study aimed to investigate the roles of renal function in determining efficacy and safety of intravenous tirofiban before endovascular treatment (EVT) for acute ischemic stroke patients with large vessel occlusion (LVO). Methods This study was a post hoc exploratory analysis of the RESCUE‐BT trial. The primary outcome was the proportion of patients achieving functional independence (modified Rankin scale 0–2) at 90 days, and the primary safety outcome was the rate of symptomatic intracranial hemorrhage (sICH). Results Among 908 individuals with available serum creatinine, decreased estimated glomerular filtration rate (eGFR) status was noted more commonly in patients with cardioembolic stroke (CE), while large artery atherosclerosis (LAA) was predominant in patients with normal renal function. In LAA with normal renal function, tirofiban was associated with higher rates of functional independence at 90 days (41.67% vs 59.80%, p = 0.003). However, for LVO patients with renal dysfunction, tirofiban did not improve functional outcomes for any of the etiologies (LAA, p = 0.876; CE, p = 0.662; others, p = 0.894) and significantly increased the risk of sICH among non‐LAA patients (p = 0.020). Mediation analysis showed tirofiban reduced thrombectomy passes (12.27%) and drug/placebo to recanalization time (14.25%) mediated its effects on functional independence. Conclusion This present study demonstrated the importance of evaluating renal function before administering intravenous tirofiban among patients with LVO who are planned to undergo EVT.

Background and Objectives Despite achieving ideal reperfusion (eTICI = 3) through endovascular treatment (EVT), some acute ischemic stroke (AIS) patients still experience poor outcomes. This study aims to evaluate the efficacy and safety of tirofiban in AIS patients with ideal reperfusion, focusing on its effects in large artery atherosclerosis (LAA) and cardioembolic (CE) stroke. Methods A total of 474 AIS patients from the RESCUE‐BT database were included. Patients were assigned to either the tirofiban or placebo group based on the treatment received. The primary outcome was favorable functional recovery at 90 days (mRS ≤2), and safety outcomes included symptomatic intracranial hemorrhage (sICH) and 90‐day mortality. Multivariable logistic regression was used to adjust for confounders, and subgroup and interaction analyses assessed tirofiban's efficacy in LAA and CE populations. Results In the overall population that achieved ideal reperfusion, Tirofiban did not improve clinical outcomes and did not increase the risk of mortality or incidence of sICH (p > 0.05). However, subgroup analysis indicated potential clinical benefits for patients with higher NIHSS scores in the LAA group, especially in the subgroup with NIHSS scores >13 (adjusted OR 4.671, 95% CI [1.545, 14.122]). No significant differences were found in the CE group. Conclusions Tirofiban showed potential benefits for LAA patients with ideal reperfusion, especially those with NIHSS scores above 13. Careful patient selection is recommended.

L‐type amino acid transporter 1 ( LAT 1), overexpressed on the membrane of various tumor cells, is a potential target for tumor‐targeting therapy. This study aimed to develop a LAT 1 ‐mediated chemotherapeutic agent. We screened doxorubicin modified by seven different large neutral amino acids. The aspartate‐modified doxorubicin (Asp‐ DOX ) showed the highest affinity (Km = 41.423 μmol/L) to LAT 1. Aspartate was attached to the N ‐terminal of DOX by the amide bond with a free carboxyl and a free amino group on the α‐carbon atom of the Asp residue. The product Asp‐ DOX was characterized by HPLC / MS . In vitro , Asp‐ DOX exerted stronger inhibition on the cancer cells overexpressing LAT 1 and the uptake of Asp‐ DOX was approximately 3.5‐fold higher than that of DOX in HepG2 cells. Pharmacokinetic data also showed that Asp‐ DOX was expressed over a longer circulation time ( t 1/2  = 49.14 min) in the blood compared to DOX alone ( t 1/2  = 15.12 min). In HepG2 and HCT 116 tumor‐bearing mice, Asp‐ DOX achieved 3.1‐fold and 6.4‐fold accumulation of drugs in tumor tissue, respectively, than those of the unmodified DOX . More importantly, treatment of tumor‐bearing mice with Asp‐ DOX showed a significantly stronger inhibition of tumor growth than mice treated with free DOX in HepG2 tumor models. Furthermore, after Asp modification, Asp‐ DOX avoided MDR mediated by P‐glycoprotein. These results suggested that the Asp‐ DOX modified drug may provide a new treatment strategy for tumors that overexpress LAT 1 and MDR 1 .

Self-assembling peptides are capable of forming a complex containing a cavity where cytotoxic agents can be wrapped in a self-assembling manner. These complexes are beneficial for improving the pharmacological properties and pharmacokinetics of cytotoxic agents, such as doxorubicin and paclitaxel. In the present study, this self-assembling feature was successfully integrated into a hexapeptide with matrix metalloproteinase (MMP)-2 specific targeting activity, producing a supramolecule possessing controlled drug release characteristics. The MMP-2 specific substrate fragment, PVGLIG, makes this supramolecule disassociate in the presence of MMP-2, and this system is considered to be a powerful tool for the treatment of tumors with high expression of MMP-2 or tumor metastasis. Our findings show that this modified self-assembling peptide with the PVGLIG fragment was able to significantly enhance specificity against HT1080 cells, a tumor cell line with high expression of MMP-2. In addition, residence time of the complex in blood was prolonged since paclitaxel was wrapped into the supramolecule. Our results suggest that the modified MMP-2 specific substrate, SAMTA7, could act as a controlled and sustained drug carrier for treatment of tumors with high expression of MMP-2 and for tumor metastasis.

IntroductionHypervirulent Klebsiella pneumoniae (hvKp) has emerged as a significant public health threat owing to its ability to cause invasive infections. This study aimed to investigate the clinical characteristics and epidemiological associations of hypervirulent Klebsiella pneumoniae (hvKp) and classical K. pneumoniae (cKp) among patients treated at a tertiary hospital in Zhuhai City, Guangdong Province, China, during the period from January to December 2022, in the context of the ongoing COVID-19 pandemic.MethodA total of 97 non-duplicated K. pneumoniae isolates and corresponding clinical data were collected. Antimicrobial susceptibility testing, hypermucoviscosity phenotyping, sequence typing, capsular serotyping, and whole-genome sequencing were performed. Hypervirulent strains were identified by the presence of the rmpA , rmpA2 , iucA , iroB , peg-344 , and peg-589 genes.ResultsAmong the 97 isolates, 40 (41.2%) were classified as hvKp. Compared with cKp, hvKp was significantly more likely to cause bacteraemia ( P < 0.05) and less likely to cause urinary tract infections ( P < 0.05). The K20 capsular serotype was significantly associated with hvKp isolates ( P < 0.05). The multidrug resistance rate among hvKp strains (22.5%) was markedly lower than that among cKp strains (56.63%), and extended-spectrum β-lactamase production was more common in cKp strains. Multilocus sequence typing identified 29 sequence types, including 24 novel types. Whole-genome sequencing of a multidrug-resistant hvKp isolate (Kp00198874) revealed an ST11-K64 strain resistant to all tested antibiotics.DiscussionThe prevalence of hvKp increased during the COVID-19 pandemic in Guangdong, China. The isolates identified in this study represent sporadic infections, and the emergence of ST11-K64 hypervirulent carbapenem-resistant K. pneumoniae (hv-CRKp) highlights the urgent need for continued surveillance and vigilance regarding hvKp-associated bacteraemia.

Overexposure to ultraviolet (UV) light is known to cause damage to the skin, leading to sunburn and photo-aging. Chemical sunscreen products may give rise to health risks including phototoxicity, photosensitivity, and photosensitivity. Natural polysaccharides have attracted considerable interests due to diverse biological activities. A novel polysaccharide isolated was purified and structurally characterized using chemical methods followed by HPLC, GLC-MS, as well as 1D and 2D NMR spectroscopy. The photoprotective effect of the EPS on UVB-induced damage was assessed using cultured keratinocytes and using C57BL/6 mouse models. The average molecular weight of the EPS was 5.48 × 10  Da, composed of glucose, mannose and galactose residues at a ratio of 2:2:1. The repeating units of the EPS were →3)-β-D-Glc (1→3) [β-D-Gal (1→2)-α-D-Glc (1→2)]-α-D-Man (1→3)-α-D-Man (1→. In cultured keratinocytes, the EPS reduced cytotoxicity and excessive ROS production induced by UVB irradiation. The EPS also exhibits an inhibitory effect on oxidative stress, inflammation, and collagen degradation found in the photodamage in mice. H NMR-based metabolomics analysis for skin suggested that the EPS partly reversed the shifts of metabolic profiles of the skin in UVB-exposed mice. The EPS exhibits skin photoprotective effects through regulating oxidative stress both and . Our findings highlight that the EPS is a potential candidate in sunscreen formulations for an efficient solution to UVB radiation.

Photolytic degradation of tetracycline (TC) was investigated in mono- and binary solute systems of Ca(II) and humic acid (HA) under UVA light emitting diode (UVA-LED) light irradiation. TC photolysis proceeded via pseudo-first-order reaction kinetics. The presence of Ca(II) significantly accelerated the degradation rate constants of TC, with the highest value at 0.0314 ± 0.0019 min−1 when the Ca(II) concentration was 5.0 mM. The promoted degradation was attributed to complexation of TC with Ca(II), which increased the light absorption. Absorbance and fluorescence measurements revealed that the strong complexation between TC and Ca(II) likely occurred via the C11 and C12 oxygen groups in the phenolic-diketone moiety of TC in nearly neutral solutions. The formation of HA-Ca(II) complex was found in the binary solute system of HA and Ca(II). Thus, the promotional effect of Ca(II) on photolysis was diminished by HA addition. The largest reduction of 32.5% in rate constants was observed with the highest Ca(II) concentration. Scavenger studies revealed that TC could undergo direct photolysis and self-sensitization by 1O2. These results suggest that the coexistence of HA and Ca(II) greatly influences the fate of TC in natural waters, which has important implications for understanding the behavior of antibiotics coexisting with other metal species and ligands.

Asthma is a common chronic inflammatory airway disease. Recent studies have reported that interleukin (IL)-33 is a potential link between the airway epithelium and Th2-type inflammatory responses, which are closely related to the progression of asthma. The IL-33 receptor, ST2, is highly expressed in group 2 innate lymphoid cells (ILC2s), Th2 cells, mast cells, eosinophils and natural killer (NK) cells. Cnidii Fructus is a Chinese herb with a long history of use in the treatment of asthma in China. Osthole is one of the major components of Cnidii Fructus. The present study examined the anti-asthmatic effects of osthole in mice and aimed to elucidate the underlying mechanisms involving the IL-33/ST2 pathway. BALB/c mice were sensitized and challenged with ovalbumin and then treated with an intraperitoneal injection of osthole (25 and 50 mg/kg). Subsequently, the airway hyper-responsiveness (AHR) and inflammation of the lungs were evaluated. The amounts of IL-4, IL-5, IL-13, interferon (IFN)-γ and IL-33 in the bronchoalveolar lavage fluid (BALF) were measured by Luminex assay and their mRNA levels in the lungs were measured by reverse transcription-quantitative PCR. The histopathology of the lungs was performed with H&E, PAS and Masson's staining. The expression of ST2 in the lungs was evaluated by immunohistochemistry. The data demonstrated that osthole markedly reduced AHR and decreased the number of eosinophils and lymphocytes in BALF. It was also observed that osthole significantly inhibited the release of Th2-type cytokines (IL-4, IL-5 and IL-13) and upregulated the IFN-γ level in BALF. Moreover, osthole significantly attenuated the IL-33 and ST2 expression in the lungs of asthmatic mice. On the whole, osthole attenuated ovalbumin-induced lung inflammation through the inhibition of IL-33/ST2 signaling in an asthmatic mouse model. These results suggest that osthole is a promising target for the development of an asthma medication.

Preeclampsia (PE), a severe hypertensive disorder during pregnancy, significantly contributes to maternal and neonatal mortality. Existing prediction biomarkers are often invasive and expensive, hindering their widespread application. This study introduces PROMPT (Preeclampsia Risk factor + Ophthalmic data + Mean arterial pressure Prediction Test), an AI-driven model leveraging retinal photography for PE prediction, registered at ChiCTR (ChiCTR2100049850) in August 2021. Analyzing 1812 pregnancies before 14 gestational weeks, we extracted retinal parameters using a deep learning system. The PROMPT achieved an AUC of 0.87 (0.83–0.90) for PE prediction and 0.91 (0.85–0.97) for preterm PE prediction using machine learning, significantly outperforming the baseline model ( p  < 0.001). It also improved detection of severe adverse pregnancy outcomes from 35% to 41%. Economically, PROMPT was estimated to avert 1809 PE cases and saved over $50 million per 100,000 screenings. These results position PROMPT as a non-invasive and cost-effective tool for prenatal care, especially valuable in low- and middle-income countries.