Search

Abstract Background Pancreatic cancer-associated fibroblasts (CAFs) play a crucial role in tumor progression and immune evasion. Asperuloside (ASP) is an iridoid glycoside with potential anti-tumor properties. This study aimed to explore the molecular mechanisms of ASP on CAFs, particularly focusing on its effects on activating transcription factor 6 (ATF6), a key regulator of endoplasmic reticulum stress. Method CAFs were treated with different concentrations of ASP (0, 1, 3, and 5 mM), and the role of ATF6 was investigated by over-expressing it in CAFs. Subsequently, western blot was used to detect ATF6, α-smooth muscle actin (α-SMA), fibroblast activating protein (FAP), and vimentin protein levels in CAFs. The collagen gel contraction assay and Transwell assay were applied to evaluate the contraction and migration ability of CAFs. In addition, the interleukin (IL)-6, C–C motif chemokine ligand (CCL)-2, and C-X-C motif chemokine ligand (CXCL)-10 levels were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results CAFs had significantly higher expression levels of α-SMA, FAP, and vimentin compared to normal fibroblasts (NFs). ASP significantly inhibited the activation, contraction, and migration of CAFs in a concentration-dependent manner. ASP treatment also reduced the expression of cytokines (IL-6, CCL2, and CXCL10) and down-regulated ATF6 levels. Over-expression of ATF6 mitigated the inhibitory effects of ASP. Conclusion ASP exerts its anti-tumor effects by down-regulating ATF6, thereby inhibiting the activation and function of pancreatic CAFs. These findings suggest that ASP could be a promising therapeutic agent for pancreatic cancer by modulating the tumor microenvironment.

Abstract Currently approved HER2-targeting antibody-drug conjugates (ADCs) for HER2-positive breast cancer (BC) are associated with safety concerns. In this multicenter, single-arm, dose-escalation (phase 1a) and dose-expansion (phase 1b) phase 1 trial (NCT03944499), patients with HER2-expressing advanced solid tumors received FS-1502 (an anti-HER2 ADC) with a 3 + 3 design in phase 1a; patients with metastatic HER2-positive BC received FS-1502 at the recommended phase 2 dose (RP2D) in phase 1b. The primary end points were dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and RP2D for phase 1a and objective response rate (ORR) for phase 1b. A total of 150 patients with HER2-expressing solid tumors (n = 5) and BC (n = 145) were enrolled (female, n = 146, 97.3%). One DLT each was reported at 3.0 and 3.5 mg/kg; the MTD was not reached. The RP2D was 2.3 mg/kg once every 3 weeks. Five (3.3%) patients experienced pneumonitis; four (2.7%) had grade 3 reversible ocular events. Of 67 HER2-positive BC patients receiving the RP2D, the best ORR was 53.7% (95% CI, 41.1-66.0%), including PRs confirmed (confirmed ORR, 37.5%) and pending for confirmation. FS-1502 was well tolerated with limited ocular and pulmonary findings and demonstrated promising antitumor activity in HER2-positive BC patients.

Public cell culture platform is an important facility in laboratory animal facilities, providing essential support for scientific research such as the development of animal tumor disease models and transgenic animals. By establishing a public cell culture experimental platform, laboratory animal centers can effectively integrate experimental animals and cell culture resources, optimizing the allocation of scientific research resources to facilitate better research outcomes. The majority of cells cultured in these platforms are used for animal experiments. Contamination or quality issues in these cells not only affect experimental results but also jeopardize the health of experimental animals, potentially leading to microbial infections and contamination of entire animal facilities. Therefore, public cell culture laboratories within experimental animal facilities impose stricter quality control measures than conventional cell culture rooms. This study takes the public cell culture platform at the Laboratory Animal Center of Shanghai Jiao Tong University as a case study to discuss management experiences, focusing on facility maintenance and management, personnel management and quality control of cell biological risk. The aim is to provide useful reference for the management of public cell culture laboratories in experimental animal facilities and other institutions.

Background: High circulatory lipoprotein(a) [Lp(a)] concentration promotes atherosclerosis; however, its efficacy in predicting the extent of atherosclerotic coronary heart disease (CHD) with coronary artery obstruction and major adverse cardiovascular events (MACEs) in diabetic patients remains questionable. This study aimed to examine whether elevated circulating Lp(a) levels exacerbate CHD and to assess their utility in predicting MACEs in individuals diagnosed with type 2 diabetes mellitus (T2DM). Methods: In total, 4332 patients diagnosed with T2DM who underwent coronary angiography (CAG) were included and categorized into two groups (CHD and non-CHD) based on the CAG results. We used a correlation analysis to explore the potential links between the levels of circulating Lp(a) and CHD severity. Cox regression analysis was performed to evaluate MACEs. Results: The concentrations of circulating Lp(a) were markedly elevated in the CHD group and positively correlated with disease severity. Our results indicate that elevated circulating Lp(a) is a crucial risk factor that significantly contributes to both the progression and severity of CHD. The differences between the two groups are evident in the risk of CHD occurrence [odds ratio (OR) = 1.597, 95 % confidence interval (CI): 1.354–1.893, p

Abstract Background Laparoscopic surgery has been endorsed by clinical guidelines for colon cancer, but not for rectal cancer on account of unapproved oncologic equivalence with open surgery. Aims We started this largest‐to‐date meta‐analysis to comprehensively evaluate the safety and efficacy of laparoscopy in the treatment of rectal cancer compared with open surgery. Materials & Methods Both randomized and nonrandomized controlled trials comparing laparoscopic proctectomy and open surgery between January 1990 and March 2020 were searched in PubMed, Cochrane Library and Embase Databases (PROSPERO registration number CRD42020211718). The data of intraoperative, pathological, postoperative and survival outcomes were compared between two groups. Results Twenty RCTs and 93 NRCTs including 216,615 patients fulfilled the inclusion criteria, with 48,888 patients received laparoscopic surgery and 167,727 patients underwent open surgery. Compared with open surgery, laparoscopic surgery group showed faster recovery, less complications and decreased mortality within 30 days. The positive rate of circumferential margin (RR = 0.79, 95% CI: 0.72 to 0.85, p

Abstract Micro-sized silicon anodes can significantly increase the energy density of lithium-ion batteries with low cost. However, the large silicon volume changes during cycling cause cracks for both organic-inorganic interphases and silicon particles. The liquid electrolytes further penetrate the cracked silicon particles and reform the interphases, resulting in huge electrode swelling and quick capacity decay. Here we resolve these challenges by designing a high-voltage electrolyte that forms silicon-phobic interphases with weak bonding to lithium-silicon alloys. The designed electrolyte enables micro-sized silicon anodes (5 µm, 4.1 mAh cm−2) to achieve a Coulombic efficiency of 99.8% and capacity of 2175 mAh g−1 for >250 cycles and enable 100 mAh LiNi0.8Co0.15Al0.05O2 pouch full cells to deliver a high capacity of 172 mAh g−1 for 120 cycles with Coulombic efficiency of >99.9%. The high-voltage electrolytes that are capable of forming silicon-phobic interphases pave new ways for the commercialization of lithium-ion batteries using micro-sized silicon anodes.

Extracts of Stevia rebaudiana Bertoni plant leaves contain a mixture of diterpene glycosides which possess high sweetness and are used as non-caloric sweeteners in foods and beverages. One of the most abundant of these steviol glycosides is Rebaudioside C (Reb C), which bears one esterified β-D-glucose and one glycosidically linked α-L-rhamnosyl-(1→2)-[β-D-glucosyl-(1→4)]-D-glucose trisaccharide. In this work, we isolated Reb C from commercial Stevia extracts using an orthogonal normal-phase × reversed-phase purification strategy. We then demonstrated that Reb C could be used as a donor substrate for enzymatic trans glycosylation reactions using chemically synthesized 1-deoxy-1-fluoro-D-glucose and 1-deoxy-1-fluoro-D-galactose donors and two engineered glycosynthases derived from Agrobacterium and Streptomyces β-glycosidases. This chemoenzymatic glucosylation/galactosylation strategy may be of use to extend the current repertoire of steviol glycosides analogues for analysis or the sensory evaluation of these novel steviol glycosides.

In search of innovative antifungal solutions for the control of plant diseases, a series of cyanoacrylate derivatives containing naphthalene groups were designed and synthesized, and their inhibition activity against four plant pathogenic fungi was evaluated. The results of in vitro bioassay revealed that some target compounds possessed obvious antifungal effect against Fusarium graminearum. As the most prominent one, compound A2 showed a inhibition rate of 98.46 % at 10 µg/mL and an EC50 value of 0.26 µg/mL, which was close to that of the positive control phenamacril (with a inhibition rate of 100 % at 10 µg/mL and EC50 value of 0.14 µg/mL). The compound A2 also markedly inhibited the growth of F. graminearum inoculated on rice leaves at 200 μg/mL with the protective and curative efficiencies of 89.03 % and 90.91 %, respectively, which were close to that of the positive control phenamacril (with the protective and curative efficiencies of 94.54 % and 96.36 %, respectively). The observation under scanning electron microscopy and measurement of relative conductivity revealed that compound A2 caused the hyphal surface become shrunken and rough, and made the cell membrane permeability increased. Molecular docking and molecular dynamics simulation analyses showed that compound A2 interacted with the key residues in the active site of myosin-5 in a similar mode as phenamacril. These results suggested that target compounds were potential myosin-5 inhibitors, they could serve as the lead compounds for further structural optimization to develop new fungicides against F. graminearum.

Introduction: Urban resilience is suffering from the challenges of climate change. The increasing volatility of climate change and its impact on urban resilience necessitates a deeper understanding of how internal organizational behaviors can contribute toward sustainable city development. Pro-environmental behavior is one of the important methods of affecting climate change and enhancing urban resilience. This study investigates how employee participation in corporate social responsibility activities promotes pro-environmental behavior and its mechanism.Methods: This research was conducted an online survey of 262 employees from 22 industries in mainland China. To mitigate the bias arising from self-reported assessments by the employees, the data were collected at two time points.Results: Empirical research reveals that employee participation in corporate social responsibility is positively related to employee pro-environmental behavior; these empirical findings not only support how psychological ownership mediates the link between corporate social responsibility participation and pro-environmental behavior but also indicate how employee engagement acts as an intermediary mechanism in enhancing this positive association. Moreover, the chain mediation effect of psychological ownership and employee engagement in the positive link between corporate social responsibility participation and pro-environmental behavior is found to be significant.Discussion: These findings not only enrich the effects of the mechanism of corporate social responsibility participation on employee behavior by introducing new theoretical perspectives but also deepen understanding of the antecedents promoting employee pro-environmental behavior, thereby contributing to the improvement of urban resilience in the face of climate change.

Abstract Background and aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) is considered a new biomarker for atherosclerosis, but its ability to predict cardiovascular outcomes has been controversial. This study aimed to address the lack of data on PCSK9, coronary heart disease (CHD) severity, and major cardiovascular events (MACEs) in patients with type 2 diabetes mellitus (T2DM). Methods A total of 2984 T2DM patients underwent selective coronary angiography, and their serum PCSK9 levels were measured using enzyme-linked immunosorbent assay. Correlation and logistic regression analyses were performed to investigate the association between PCSK9 expression and CHD severity. This study used Cox regression analysis to assess the association between circulating PCSK9 levels and the risk of MACEs. Results Circulating PCSK9 levels were significantly higher in the CHD group than in the non-CHD group [554.62 (265.11) ng/mL vs. 496.86 (129.05) ng/mL, p

AbstractContext Atopic dermatitis (AD) is a common inflammatory skin disease characterized with hyperactivation of type 2 T helper (Th2) immune responses. Icariin is a flavonoid glucoside with anti-inflammatory activities, which has been used to treat multiple diseases.Objective The present study investigates the underlying mechanisms by which icariin regulates Th2 responses and AD development.Materials and methods BALB/c mice were induced by DNFB to establish AD models, and injected with or without 10 mg/kg icariin for 2 weeks (i.p., daily). CD4+T cells were induced by Th2 condition to simulate AD in vitro, and also treated with or without 100 µM icariin.Results Icariin ameliorated AD-like skin lesion, manifested as a significant decrease in dermatitis scores (from 8.00 ± 1.00 to 3.67 ± 0.58), serum IgE levels (from 3119.15 ± 241.81 to 948.55 ± 182.51 ng/mL), epidermal thickness (from 93.86 ± 4.61 to 42.67 ± 2.48 µm) and infiltration of mast cells (from 60.67 ± 3.21 cells to 36.00 ± 2.65 cells). Also, icariin inactivated NLRP3 inflammasome, inhibited Th2 skewing, reduced lncRNA MALAT1 expression, but elevated miR-124-3p expression in vivo and in vitro. MALAT1 increased NLRP3 expression through targeting miR-124-3p. Knockdown of MALAT1 repressed NLRP3 inflammasome activation and mitigated Th1/Th2 imbalance in Th2-conditioned CD4+T cells, whereas both MALAT1 overexpression and miR-124-3p inhibition ablated the inhibitory effects of icariin on Th2 immune responses.Discussion and conclusions The findings further improve our understanding of the mechanism by which icariin affects AD progression, and highlights the potential of icariin in the treatment of AD.

Abstract Background and Objectives This study was conducted to investigate the effect of high-fat meals on the pharmacokinetics (PK) and safety profile of SAF-189s, a novel ALK/ROS1 inhibitor. Methods This was a single-center, phase I, open-label, crossover study in which healthy adults (≥18 years) were randomized (1:1) to two sequences of SAF-189s administration (fasted-fed or fed-fasted) separated by a 14-day washout. After a ≥10-h overnight fast, volunteers received SAF-189s 160 mg orally in a fasted state or 30 min after a high-fat, high-calorie meal. Similarity of pharmacokinetic parameters was concluded if the 90% CI for the geometric mean ratio (GMR) between the fed and fasted group fell within the predefined range of 0.80–1.25. Results In total, 24 subjects were enrolled and 23 completed the study. SAF-189s maximum plasma concentration (C max; GMR: 109.1% [90% CI 103.1–115.4]) was comparable under fed (high-fat meal, n = 24) versus fasted (n = 23) conditions, with no effect on area under the plasma concentration–time curve from time 0 to t (AUC0-t; GMR: 105.1% [90% CI 100.3–110.2]) and AUC from time 0 to infinity (AUC0-∞; GMR: 105.5% [90% CI, 100.6–110.6]). In both groups, the median time to maximum plasma concentration (t max) was around 6 h and mean plasma half-life (t ½) was around 35 h. Fed administration led to a lower incidence of treatment-emergent adverse events (TEAEs; 29.2% vs 54.2%), including gastrointestinal disorders (4.2% vs 41.7%) and headache (0.0% vs 12.5%), versus fasted administration. Conclusions A high-fat meal had minimal effect on the pharmacokinetic profile of SAF-189s compared with a fasted state following a single dose of 160 mg. Administration with a high-fat meal led to a lower incidence of TEAEs.