Efficacy and safety of intranasal insulin on postoperative cognitive dysfunction in elderly patients after laparoscopic radical resection of colorectal cancer: a double-blind pilot study.

Objective: To evaluate the efficacy and safety of intranasal insulin on postoperative cognitive dysfunction (POCD) in elderly patients after laparoscopic radical resection of colorectal cancer. Methods: Older patients scheduled for laparoscopic radical resection of colorectal cancer at Beijing Luhe Hospital, Capital Medical University, between August 2023 and November 2023, were enrolled in this double-blind pilot study. Patients were randomized to the control and insulin groups at a 1:1 ratio. The primary outcome was the rate of POCD at postoperative 7 days. Results: A total of 61 patients (30 in the insulin group) were analyzed. The insulin group had a significantly lower POCD rate compared with the control group at postoperative day 7 [4(13.3%) vs. 12 (38.7%), p = 0.024]. The serum levels of IL-6, TNF-α and S100ß at T2-5 in the insulin group were significantly lower than those of the control group (IL-6: mean difference at T2, -4.14, p = 0.036; T3, -3.84, p = 0.039; T4, -3.37, p = 0.013; T5, -2.57, p = 0.042; TNF-α: mean difference at T2, -3.19, p = 0.002; T3, -2.35, p = 0.028; T4, -2.30, p = 0.019; T5, -1.96, p = 0.0181; S100ß: mean difference at T2, -8.30, p = 0.019; T3, -23.95, p = 0.020; T4, -20.01, p = 0.023; T5, -17.67, p = 0.010). No insulin allergic reactions, nasal irritation, or hypoglycemic reactions were observed in either of the groups. Conclusion: Intranasal insulin may decrease the risk of POCD and inhibit the elevated serum IL-6, TNF-α, and S100ß levels in elderly patients after laparoscopic radical resection of colorectal cancer, which proves that intranasal insulin may be a promising therapeutic option for POCD. Clinical trial registration: Identifier, ChiCTR2300074423.

High-resolution genome mapping and functional dissection of chlorogenic acid production in Lonicera maackii.

Amur honeysuckle (Lonicera maackii) is a widely used medicinal plant of the Caprifoliaceae family that produces chlorogenic acid. Research on this plant mainly focuses on its ornamental value and medicinal compounds, but a reference genome sequence and molecular resources for accelerated breeding are currently lacking. Herein, nanopore sequencing and high-throughput chromosome conformation capture (Hi-C) allowed a chromosome-level genome assembly of L. maackii (2n = 18). A global view of the gene regulatory network involved in the biosynthesis of chlorogenic acid and the dynamics of fruit coloration in L. maackii was established through metabolite profiling and transcriptome analyses. Moreover, we identified the genes encoding hydroxycinnamoyl-CoA quinate transferase (LmHQT) and hydroxycinnamoyl-CoA shikimic/quinate transferase (LmHCT), which localized to the cytosol and nucleus. Heterologous overexpression of these genes in Nicotiana benthamiana leaves resulted in elevated chlorogenic acid contents. Importantly, HPLC analyses revealed that LmHCT and LmHQTs recombinant proteins modulate the accumulation of chlorogenic acid (CGA) using quinic acid and caffeoyl CoA as substrates, highlighting the importance of LmHQT and LmHCT in CGA biosynthesis. These results confirmed that LmHQTs and LmHCT catalyze the biosynthesis of CGA in vitro. The genomic data presented in this study will offer a valuable resource for the elucidation of CGA biosynthesis and facilitating selective molecular breeding.

How does the internal distribution of microplastics in Scylla serrata link with the antioxidant response in functional tissues?

Crabs can live in diverse lifestyles in both water and benthic environments, which are the basin of microplastics (MPs) inputs. Edible crabs with large consuming quantity, e.g., Scylla serrata were subjected to accumulate MPs in their tissues from surrounding environments and generate biological damages. However, no related research has been conducted. In order to accurately assess the potential risks to both crabs and humans consuming MPs contaminated crabs, S. serrata were exposed to different concentrations (2, 200 and 20,000 µg/L) of polyethylene (PE) microbeads (10-45 µm) for 3 days. The physiological conditions of crabs and a series of biological responses, including DNA damage, antioxidant enzymes activities and their corresponding gene expressions in functional tissues (gills and hepatopancreas) were investigated. PE-MPs accumulated in all tissues of crabs with concentration- and tissue-dependent manner, which was assumed to be via the internal distribution initialized by gills' respiration, filtration and transportation. Significantly increased DNA damages were observed in both gills and hepatopancreas under exposures, however, the physiological conditions of crabs showed no dramatic alterations. Under low and middle concentration exposures, gills energetically activated the first line of antioxidant defense to against oxidative stress, e.g., superoxide dismutase (SOD) and catalase (CAT), but lipid peroxidation damage still occurred under high concentration exposure. In comparison, SOD and CAT composed antioxidant defense in hepatopancreas tended to collapse under severe MPs exposure and the defense mechanism attempted to switch to the secondary antioxidant response by compensatively stimulating the activities of glutathione S-transferase (GST), glutathione peroxidase (GPx) and the content of glutathione (GSH). The diverse antioxidant strategies in gills and hepatopancreas were proposed to be closely related to the accumulation capacity of tissues. The results confirmed the relation between PE-MPs exposure and antioxidant defense in S. serrata, and will help to clarify the biological toxicity and corresponding ecological risks.

Assessment of sulfamethoxazole toxicity to marine mussels (Mytilus galloprovincialis): Combine p38-MAPK signaling pathway modulation with histopathological alterations.

Sulfamethoxazole (SMX), is a ubiquitous antibiotic in the aquatic environment and received concerns on its health hazards, especially its sub-lethal effects on non-target organisms which were remained largely unknown. In the present study, in order to investigate SMX induced tissue damages and reveal underlying mechanisms, marine mussels, Mytilus galloprovincialis were challenged to SMX series (0.5, 50 and 500 µg/L) for six-days followed by six-day-recovery. Comprehensive histopathological alteration (including qualitative, semi-quantitative and quantitative indices), together with transcriptional and (post-) translational responses of key factors (p38, NFκB and p53) in the p38-MAPK signaling pathway were analyzed in gills and digestive glands. Tissue-specific responses were clearly investigated with gills showing more prompt responses and digestive glands showing higher tolerance to SMX. The histopathology showed that SMX triggered inflammatory damages in both tissues and quantitative analysis revealed more significant responses, suggesting its potential as a valuable health indicator. SMX activated expressions of p38, NFκB and p53 at transcriptional and (post-) translational levels, especially after exposed to low level SMX, evidenced by p38 coupled with NFκB/p53 regulation on immunity defense in mussels. Less induction of targeted molecules under severe SMX exposure indicated such signaling transduction may not be efficient enough and can result in inflammatory damages. Taken together, this study expanded the understanding of aquatic SMX induced health risk in marine mussels and the underlying regulation mechanism through p38 signaling transduction.

Prevalence, characteristics, and consequences of verbal and physical violence against healthcare staff in Chinese hospitals during 2010-2020.

OBJECTIVES: This study investigated the characteristics of workplace violence (WPV) against Chinese healthcare staff and their casualties after severe physical violence (PV). METHODS: We scrutinized medical WPV incidents reported online and analyzed information on timing, location, violence, criminal incentives, and casualties following severe PV in China from 2010 to 2020. RESULTS: WPVs were mostly committed by young and middle-aged male family members of the patients, especially in the emergency department (49.1%), and mostly associated with dissatisfaction with treatment effect (28.9%) in general. High medical costs (62.5%) were the leading cause of verbal violence (VV), whereas men predominantly committed PV (OR = 4.217, 95% CI: 1.439-12.359) owing to dissatisfaction with the healthcare staff's attitude (P < 0.001). The victims were security personnel in most cases (81.1%). Nurses were generally more likely to experience PV (P < 0.05), while doctors were more likely to experience lethal PV (OR = 4.732, 95% CI: 1.42-15.772), which mostly happened in oncology (P < 0.05) and committed by visitors (P < 0.001). Slight injuries and mortality were more likely to be inflicted by being rejected for unreasonable demands and disappointed with the treatment effect (P < 0.05). CONCLUSIONS: Medical WPV has numerous reasons, locations, and diverse victims and offenders. Some severe WPVs have serious consequences. Therefore, it is recommended for the concerned authorities to adopt effective steps for appropriate legislative, security, and conflict-resolution measures.

Expression characteristics of long non-coding RNA in colon adenocarcinoma and its potential value for judging the survival and prognosis of patients: bioinformatics analysis based on The Cancer Genome Atlas database.

Background: To investigate the expression characteristics of long non-coding RNA (lncRNA) in colon adenocarcinoma (COAD) and its potential value in predicting the prognosis of patient survival. Methods: We downloaded COAD-related RNA sequencing (RNA-seq) data and patient survival data from The Cancer Genome Atlas (TCGA). The data were analyzed for lncRNA expression differences, subjected to Cox regression analysis for survival rate, and Kaplan-Meier (KM) survival curves were plotted to analyze the role of the key genes related to prognostic survival by pathway enrichment analysis. Results: The data of 494 COAD clinical samples from TCGA were analyzed; 204 lncRNAs were differentially expressed, 156 were up-regulated, and 48 were down-regulated. The 10 genes with the most significant expression differences were Linc02418, Blacat1, ELFN1-AS1, CRNDE, AC002384.1, AL353801.1, LINC01645, AC073283.2, AC087379.1, and LINC00484. Cox regression analysis of 204 lncRNA genes showed that 23 lncRNA genes with significant effects on the prognosis and survival rate of COAD patients were obtained when P<0.05 was used as the threshold. With P≤0.001 as the threshold, the KM curves of 4 genes (Linc02257, Linc02474, Ac010789.1, Ac083967.1) were statistically significant (P<0.05). The gene Linc02257 was selected for Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and it was revealed that the inheritance of Linc02257-regulated gene expression was closely related to tumor development, such as collagen-containing extracellular matrix, organogenesis, activity of membrane protein receptors, and ion channel activity. The signaling pathways regulated by Linc02257 were also closely related to tumors, such as neuroactive ligand-receptor interaction, the PI3K-AKT signaling pathway, calcium signaling pathway, and protein digestion and absorption. Conclusions: In COAD, lncRNA is differentially expressed and plays an important role in the disease regulation. It has potential application value in the diagnosis, targeted therapy, and prognosis of COAD patients.

Prophylactic Effect of Simultaneous Placement of Mesh on Incidence of Parastomal Hernia After Miles' Surgical Resection of Colorectal Cancer: A Prospective Study.

INTRODUCTION: To assess the prophylactic effect of simultaneous placement of mesh and the incidence of parastomal hernia (PSH) after abdominoperineal resection of rectal cancer. METHODS: This study included real-world data of 56 surgically resected patients with colorectal cancer who were consecutively assigned to two groups: control (no mesh, n = 32) and experimental (received mesh, n = 24). An artificial patch was placed under the tunica vaginalis of rectus abdominis for patients in the experimental group, whereas those in the control group received routine sigmoidostomy. The median follow-up time was >20 mo. The difference in hazards function was analyzed by cox regression analysis. The Kaplan-Meir analysis was used to determine the survival curves. A P value of <0.05 was considered as significant. RESULTS: The postoperative incidence rate of PSH was lower in the experimental (41.7%) group than in the control group (71.9%; P = 0.045). The PSH postoperative time in the experimental group was significantly delayed compared to the control group (48 mo versus 10 mo; P < 0.001). The risk of progression from H1 to H2 was less in the experimental group compared to the control group (49.28% versus 60.86%; P = 0.14). CONCLUSIONS: Prophylactic mesh placement significantly prolonged postoperative time for the recurrence of PSH. The incidence of recurrence of H2 (severe PSH) requiring secondary surgical repair was also reduced.

Total Synthesis of the Monomeric Unit of Lomaiviticin A.

The architecturally symmetrical and synthetically challenging marine natural products lomaiviticins A and B present alluring synthetic targets due to their molecular complexity, potent antitumor properties, and natural scarcity. Herein, we report the total synthesis of the fully glycosylated monomeric unit of lomaiviticin A, monolomaiviticin A. The retrosynthetically derived synthetic strategy relied on an intramolecular palladium-catalyzed coupling reaction to complete the tetracyclic aglycon scaffold and gold-promoted glycosylations to install the synthetically challenging α- and ß-glycoside moieties of the target molecule. This accomplishment paves a path for the eventual total synthesis of lomaiviticins A and B and opens opportunities for biological investigations within this family of compounds.

Synthesis and Biological Evaluation of Shishijimicin A-Type Linker-Drugs and Antibody-Drug Conjugates.

Our previous studies with shishijimicin A resulted in the total synthesis of this scarce marine natural product and a number of its simpler analogues endowed with picomolar potencies against certain cancer cell lines. Herein, we describe the design, synthesis, and biological evaluation of four linker-drugs, anticipating the construction of antibody-drug conjugates (ADCs) as the ultimate goal of this research program. Using a common payload, the assembly of these linker-drugs utilized different linkers and attachment points, providing opportunities to probe the optimal molecular design of the intended ADCs as targeted cancer therapies. In the course of ADC generation and in vitro evaluation, we identified two linker-drugs with a promising in vitro plasma stability profile and excellent targeted cytotoxicity and specificity. Conjugation of shishijimicin A enediyne payloads through their phenolic moiety represents a novel approach to enediyne ADC creation, while the pharmacological profiles of at least two of the generated ADCs compare well with the profiles of the corresponding clinically approved ADC Kadcyla.

Regorafenib Combined With Sirolimus Achieves Successful Treatment of Diffuse Double Lung Metastasis After Liver Transplantation in Giant Liver Cancer Beyond Transplantation Criteria: A Case Report.

The treatment of hepatocellular carcinoma after liver transplantation (LT) is controversial because of its high recurrence rate and low survival rate. Here, we report a case of early diffuse bilateral lung metastasis after LT beyond the Milan transplantation criteria (d = 18 cm, α-fetoprotein >24,000 ng/mL) that successfully achieved 1-year tumor-free remission survival with sirolimus combined with regorafenib. The donor source of the liver is legal, and this study followed the guidelines of the Helsinki Congress in this LT. To the best of our knowledge, this is the first report of the use of regorafenib as a first-line agent combined with sirolimus to treat recurrent hepatocellular carcinoma after LT, and this case expands the indications for LT.

Feasibility of nanoscale zero-valent iron (nZVI) for enhanced biological treatment of organic dyes.

Biodegradation of recalcitrant organic contaminants such as organic dyes is a fundamental challenge in wastewater treatment. We report herein the integration of nanoscale zero-valent iron (nZVI) with membrane bioreactors (nZVI-bio system) to achieve enhanced degradation of Congo red (CR) in wastewater. nZVI pretreatment converts the large and bio-recalcitrant CR molecules into smaller and more biodegradable organic compounds in continuous flow stirred tank reactors (CFSTR). A nZVI-bio system was experimented continuously for 52 d with a color removal efficiency of 99% and a reduction of chemical oxygen demand (COD) from 167 mg L-1 to less than 70 mg L-1. However, a conventional biotreatment system treating identical wastewater achieved color removal efficiency of just 30-70% and the COD reduction to 116 mg L-1. This suggests that integrated nZVI-bio system has potential for the treatment of recalcitrant organic dyes. On-line measurements of pH and redox potential in the CSFTR can be conveniently used to monitor and regulate treatment performance.

DNA Binding and Cleavage Modes of Shishijimicin A.

Although shishijimicin A and its extreme potencies against an array of cancer cell lines have been known for more than a decade, its assumed DNA-cleaving mechanism has not been substantiated as yet. Herein we report studies that reveal binding and scission of double-stranded DNA by shishijimicin A. The results of these studies support the proposed hypothesis that DNA strand scissions are caused by 1,4-benzenoid diradicals formed by Bergman cycloaromatization of the enediyne core of shishijimicin A upon activation by thiols. In addition, double-stranded supercoiled DNA-cleavage experiments with shishijimicin A in competition with known minor groove binders, UV spectroscopic studies, and electrophoretic analysis were utilized to clarify the binding mode of the molecule to DNA. These investigations indicate that shishijimicin A binds to the minor groove of double-stranded DNA and that its ß-carboline moiety plays a role in the binding through intercalation. In addition, due to the fact that naked linker regions of DNA in the interphase and metaphase of eukaryotic cells are unprotected by histone proteins during entire cell cycles and because these unprotected regions of DNA are vulnerable to attack by DNA binders, it was concluded that the observed double-strand DNA cleavage and very low sequence selectivity by shishijimicin A may account for its extraordinary cytotoxicity.

Streamlined Total Synthesis of Shishijimicin A and Its Application to the Design, Synthesis, and Biological Evaluation of Analogues thereof and Practical Syntheses of PhthNSSMe and Related Sulfenylating Reagents.

Shishijimicin A is a scarce marine natural product with highly potent cytotoxicities, making it a potential payload or a lead compound for designed antibody-drug conjugates. Herein, we describe an improved total synthesis of shishijimicin A and the design, synthesis, and biological evaluation of a series of analogues. Equipped with appropriate functionalities for linker attachment, a number of these analogues exhibited extremely potent cytotoxicities for the intended purposes. The synthetic strategies and tactics developed and employed in these studies included improved preparation of previously known and new sulfenylating reagents such as PhthNSSMe and related compounds.

Total Synthesis and Full Structural Assignment of Namenamicin.

Namenamicin is a rare natural product possessing potent cytotoxic properties that may prove useful as a lead compound for payloads of antibody-drug conjugates (ADCs). Its scarcity, coupled with the uncertainty of its full absolute configuration, elevates it to an attractive synthetic target. Herein we describe the total synthesis of the two C7'-epimers of namenamicin and assign its complete structure, opening the way for further chemical and biological studies toward the discovery of potent payloads for ADCs directed toward targeted cancer therapies.

Streamlined Total Synthesis of Trioxacarcins and Its Application to the Design, Synthesis, and Biological Evaluation of Analogues Thereof. Discovery of Simpler Designed and Potent Trioxacarcin Analogues.

A streamlined total synthesis of the naturally occurring antitumor agents trioxacarcins is described, along with its application to the construction of a series of designed analogues of these complex natural products. Biological evaluation of the synthesized compounds revealed a number of highly potent, and yet structurally simpler, compounds that are effective against certain cancer cell lines, including a drug-resistant line. A novel one-step synthesis of anthraquinones and chloro anthraquinones from simple ketone precursors and phenylselenyl chloride is also described. The reported work, featuring novel chemistry and cascade reactions, has potential applications in cancer therapy, including targeted approaches as in antibody-drug conjugates.

Reduction of oxidative damages induced by titanium dioxide nanoparticles correlates with induction of the Nrf2 pathway by GSPE supplementation in mice.

Titanium dioxide nanoparticles (TiO2 NPs) are widely used to additives in cosmetics, pharmaceuticals, paints and foods. Recent studies have demonstrated that TiO2 NPs increased the risk of cancer and the mechanism might relate with oxidative stress. Grape seed procyanidin extract (GSPE) is a natural compound which has been demonstrated to possess a wide array of pharmacological and biochemical actions, including anti-inflammatory, anti-carcinogenic, and antioxidant properties. Our data show that GSPE prevents the changes of histopathology and biomarkers in heart, liver and kidney that occur in mice exposed to TiO2 NPs. After pretreatment with GSPE, the DNA damage, reactive oxygen species (ROS) generation and malondialdehyde (MDA) content in mice exposed to TiO2 NPs had statistically significant decreases in dose dependent manners. GSPE increased the expression of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), NAD(P)H dehydrogenase[quinine] 1(NQO1), heme oxygenase 1 (HO-1) and glutamate-cysteine ligase catalytic subunit (GCLC). We conclude that grape seed procyanidin extract prevents the majority of tissue and molecular damage resulting from nanoparticle treatment. The protective effect of GSPE may be due to its strong antioxidative activities which related with the activated Nrf2 and its down-regulated genes including NQO1, HO-1 and GCLC.

Total Synthesis of Shishijimicin A.

The total synthesis of the rare but extremely potent antitumor agent shishijimicin A has been achieved via a convergent strategy involving carboline disaccharide 3 and hydroxy enediyne thioacetate 4.

Transmyocardial revascularization and vascular endothelial growth factor administration enhance effect of cell transplantation for myocardial infarct repair in rats.

OBJECTIVE: To test the hypothesis that transmyocardial revascularization and vascular endothelial growth factor (VEGF) administration would enhance cell transplantation effect for myocardial infarct. METHODS: After ligation of left anterior descending coronary artery, the recipient rats were treated with transmyocardial revascularization. Ten minutes after transmyocardial revascularization, recombinant murine VEGF165 was injected into the clot of the drilling channel and the myocardium bordering the channel. Two weeks after transmyocardial revascularization, differentiated cells from embryo stem cells were injected into the infarcted myocardium and vascular endothelial growth factor was injected again in the same dose. Four weeks after the differentiated cells were grafted, cardiac function was assessed by hemodynamic measurements. Capillary density and infarct size in the infarct region were measured with a previous experimental method. Graft histology and morphology were also evaluated. RESULTS: Four weeks after the differentiated cells were grafted, myocardial infarct rats treated with transmyocardial revascularization and vascular endothelial growth factor showed a significantly higher cardiac function in hemodynamic measurements (P<0.01) than other control groups. A significant increase in capillary density and reduction in infarct size were observed in the infarct hearts of the myocardial infarct rats under combination therapy (P<0.01). CONCLUSIONS: Before differentiated cell transplantation, transmyocardial revascularization and vascular endothelial growth factor administration caused an angiogenesis effect to enhance neovascularization. It may be superior in attenuating the progression of cardiac dysfunction in the rat model compared with the myocardial infarct rat transplanted cell alone.

Pretreatment with transmyocardial revascularization might improve ischemic myocardial function performed with cell transplantation.

BACKGROUND: Cells transplanted into the myocardial infarct areas might be lost because of the lack of blood supply to these myocardium areas. The hypothesis that pretreatment with angiogenic therapy induced by transmyocardial revascularization (TMR) might improve ischemic myocardial function, followed by cell transplantation was tested. METHODS AND RESULTS: After the ligation of the left anterior descending coronary artery, rats were treated with TMR. Two weeks, embryonic stem cells were transplanted into an injured heart. Four weeks after cell transplantation, cardiac function was assessed by homodynamic measurements. Capillary density and infarct size in the infarct myocardium were measured by using a previous experimental method. Graft histology and morphology was also evaluated. Four weeks after the operation, myocardial infarct (MI) rats treated with TMR and cell transplantation showed significantly higher cardiac function in hemodynamic measurements (p < 0.01) than that of MI rats receiving cell transplantation or TMR alone. A significant increase in capillary density and reduction in infarct size was observed in the MI rats that received a combined therapy (p < 0.01). CONCLUSION: Pretreatment of an infarct region of the heart with angiogenesis induced by TMR can enhance the efficacy of a cell graft and attenuate the progression of cardiac dysfunction in the rat model.