Discovery of Dolutegravir Derivative against Liver Cancer via Inducing Autophagy and DNA Damage.

We introduced a terminal alkyne into the core structure of dolutegravir, resulting in the synthesis of 34 novel dolutegravir-1,2,3-triazole compounds through click chemistry. These compounds exhibited remarkable inhibitory activities against two hepatocellular carcinoma cell lines, Huh7 and HepG2. Notably, compounds 5e and 5p demonstrated exceptional efficacy, particularly against Huh7 cells, with IC50 values of 2.64 and 5.42 µM. Additionally, both compounds induced apoptosis in Huh7 cells, suppressed tumor cell clone formation, and elevated reactive oxygen species (ROS) levels, further promoting tumor cell apoptosis. Furthermore, compounds 5e and 5p activated the LC3 signaling pathway, inducing autophagy, and triggered the γ-H2AX signaling pathway, resulting in DNA damage in tumor cells. Compound 5e exhibited low toxicity, highlighting its potential as a promising anti-tumor drug.

Development of Glycosylation-Modified DPPA-1 Compounds as Innovative PD-1/PD-L1 Blockers: Design, Synthesis, and Biological Evaluation.

In the context of peptide drug development, glycosylation plays a pivotal role. Accordingly, L-type peptides were synthesized predicated upon the PD-1/PD-L1 blocker DPPA-1. Subsequent glycosylation resulted in the production of two distinct glycopeptides, D-glu-LPPA-1 and D-gal-LPPA-1, by using D-glucose (D-glu) and D-galactose (D-gal), respectively, during glycosylation. Both glycopeptides significantly inhibited the interaction between PD-1 and PD-L1, and the measured half maximal inhibitory concentrations (IC50s) were 75.5 µM and 101.9 µM for D-glu-LPPA-1 and D-gal-LPPA-1, respectively. Furthermore, D-gal-LPPA-1 displayed a pronounced ability to restore T-cell functionality. In an MC38 tumor-bearing mouse model, D-gal-LPPA-1 demonstrated a significant inhibitory effect. Notably, D-gal-LPPA-1 substantially augmented the abundance and functionality of CD8+ T cells in the tumor microenvironment. Additionally, in the lymph nodes and spleens, D-gal-LPPA-1 significantly increased the proportion of CD8+ T cells secreting interferon-gamma (IFN-γ). These strong findings position D-gal-LPPA-1 as a potent enhancer of the antitumor immune response in MC38 tumor-bearing mice, underscoring its potential as a formidable PD-1/PD-L1 blocking agent.

Mo2 N-ZrO2 Heterostructure Engineering in Freestanding Carbon Nanofibers for Upgrading Cycling Stability and Energy Efficiency of Li-CO2 Batteries.

Li-CO2 batteries have attracted considerable attention for their advantages of CO2 fixation and high energy density. However, the sluggish dynamics of CO2 reduction/evolution reactions restrict the practical application of Li-CO2 batteries. Herein, a dual-functional Mo2 N-ZrO2 heterostructure engineering in conductive freestanding carbon nanofibers (Mo2 N-ZrO2 @NCNF) is reported. The integration of Mo2 N-ZrO2 heterostructure in porous carbons provides the opportunity to simultaneously accelerate electron transport, boost CO2 conversion, and stabilize intermediate discharge product Li2 C2 O4 . Benefiting from the synchronous advantages, the Mo2 N-ZrO2 @NCNF catalyst endows the Li-CO2 batteries with excellent cycle stability, good rate capability, and high energy efficiency even under high current densities. The designed cathodes exhibit an ultrahigh energy efficiency of 89.8% and a low charging voltage below 3.3 V with a potential gap of 0.32 V. Remarkably, stable operation over 400 cycles can be achieved even at high current densities of 50 µA cm-2 . This work provides valuable guidance for developing multifunctional heterostructured catalysts to upgrade longevity and energy efficiency of Li-CO2 batteries.

Isoquercetin regulates SREBP-1C via AMPK pathway in skeletal muscle to exert antihyperlipidemic and anti-inflammatory effects in STZ induced diabetic rats.

Diabetes mellitus (DM) is a cluster of metabolic diseases that exhibits high blood glucose levels accompanied by hyperlipidemia and inflammation. DM is the primary risk factor contributes majorly to cardiovascular disease (CVD) mediated morbidity and mortality. The incidence of dyslipidemia seems to attribute considerably to the initiation of CVDs. The beneficial action of isoquercetin on hyperlipidemia and related signaling pathways are not documented yet, hence we decide to carry out this study. The experimental rats were divided into five groups: Group 1, control rats; group 2, isoquercetin control (40 mg/kg b.w); group 3, diabetic rats (STZ-40 mg/kg b.w); group 4, diabetic + isoquercetin (40 mg/kg b.w); and group 5, diabetic + glibenclamide (600 µg/kg b.w). The animals were sacrificed at the end of the experimental duration of 45 days. Results of our analysis reveal that isoquercetin have a major impact on the tissue lipid profile, isoquercetin strongly regulates the expression of various lipid-metabolizing enzymes, C-reactive protein, expression of various inflammatory genes, SREBP-1C genes and proteins and AMP-activated protein kinase-α (AMPK) signaling pathway genes and proteins. Results recommend that isoquercetin can be effective in mitigating the consequences of hyperlipidemia and DM.

Discovery of gefitinib-1,2,3-triazole derivatives against lung cancer via inducing apoptosis and inhibiting the colony formation.

A series of 20 novel gefitinib derivatives incorporating the 1,2,3-triazole moiety were designed and synthesized. The synthesized compounds were evaluated for their potential anticancer activity against EGFR wild-type human non-small cell lung cancer cells (NCI-H1299, A549) and human lung adenocarcinoma cells (NCI-H1437) as non-small cell lung cancer. In comparison to gefitinib, Initial biological assessments revealed that several compounds exhibited potent anti-proliferative activity against these cancer cell lines. Notably, compounds 7a and 7j demonstrated the most pronounced effects, with an IC50 value of 3.94 ± 0.17 µmol L-1 (NCI-H1299), 3.16 ± 0.11 µmol L-1 (A549), and 1.83 ± 0.13 µmol L-1 (NCI-H1437) for 7a, and an IC50 value of 3.84 ± 0.22 µmol L-1 (NCI-H1299), 3.86 ± 0.38 µmol L-1 (A549), and 1.69 ± 0.25 µmol L-1 (NCI-H1437) for 7j. These two compounds could inhibit the colony formation and migration ability of H1299 cells, and induce apoptosis in H1299 cells. Acute toxicity experiments on mice demonstrated that compound 7a exhibited low toxicity in mice. Based on these results, it is proposed that 7a and 7j could potentially be developed as novel drugs for the treatment of lung cancer.

Feeding cessation and antibiotics improve clinical symptoms and alleviate gut and systemic inflammation in preterm pigs sensitive to necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a microbiota- and feeding-related gut inflammatory disease in preterm infants. The standard of care (SOC) treatment for suspected NEC is antibiotic treatment and reduced enteral feeding, but how SOC treatment mitigates NEC remains unclear. We explored whether SOC treatment alone or combined with an anti-inflammatory protein (inter-alpha inhibitor protein, IAIP) supplementation improves outcomes in a preterm piglet model of formula-induced NEC. Seventy-one cesarean-delivered preterm piglets were initially fed formula, developing NEC symptoms by day 3, and then randomized into CON (continued feeding) or SOC groups (feeding cessation and antibiotics), each with or without human IAIP (2×2 factorial design). By day 5, IAIP treatment did not significantly influence outcomes, whereas SOC treatment effectively reduced NEC lesions, diarrhea, and bloody stools. Notably, SOC treatment improved gut morphology and function, dampened gut inflammatory responses, altered the colonic microbiota composition, and modulated systemic immune responses. Plasma proteomic analysis revealed the effects of SOC treatment on organ development and systemic inflammatory responses. Collectively, these findings suggest that SOC treatment significantly prevents NEC progression in preterm piglets via effects on gut structure, function, and microbiota, as well as systemic immune and inflammatory responses. Timely feeding cessation and antibiotics are critical factors in preventing NEC progression in preterm infants, while the benefits of additional human IAIP treatment remain to be established.

Regulation of host metabolism and defense strategies to survive neonatal infection.

Two distinct defense strategies, disease resistance (DR) and disease tolerance (DT), enable a host to survive infectious diseases. Newborns, constrained by limited energy reserves, predominantly rely on DT to cope with infection. However, this approach may fail when pathogen levels surpass a critical threshold, prompting a shift to DR that can lead to dysregulated immune responses and sepsis. The mechanisms governing the interplay between DR and DT in newborns remain poorly understood. Here, we compare metabolic traits and defense strategies between survivors and non-survivors in Staphylococcus epidermidis (S. epidermidis)-infected preterm piglets, mimicking infection in preterm infants. Compared to non-survivors, survivors displayed elevated DR during the initial phase of infection, followed by stronger DT in later stages. In contrast, non-survivors showed clear signs of respiratory and metabolic acidosis and hyperglycemia, together with exaggerated inflammation and organ dysfunctions. Hepatic transcriptomics revealed a strong association between the DT phenotype and heightened oxidative phosphorylation in survivors, coupled with suppressed glycolysis and immune signaling. Plasma metabolomics confirmed the findings of metabolic regulations associated with DT phenotype in survivors. Our study suggests a significant association between the initial DR and subsequent DT, which collectively contributes to improved infection survival. The regulation of metabolic processes that optimize the timing and balance between DR and DT holds significant potential for developing novel therapeutic strategies for neonatal infection.

Design and synthesis of cabotegravir derivatives bearing 1,2,3-triazole and evaluation of anti-liver cancer activity.

Based on the structure of the anti-HIV drug cabotegravir, we introduced 1,2,3-triazole groups with different substituents to obtain 19 cabotegravir derivatives and tested their activity against HepG2 cells. The proliferation of HepG2 cells was examined following treatment with derivatives. Most of the compounds demonstrated significant inhibitory effects, particularly compounds KJ-5 and KJ-12 with IC50 values of 4.29 ± 0.10 and 4.07 ± 0.09 µM, respectively. Furthermore, both compounds 5 and 12 significantly caused cell apoptosis, G2/M arrest, and DNA damage, and suppressed invasion and migration in a concentration-dependent manner. In addition, KJ-5 and KJ-12 could trigger apoptosis via the mitochondrial pathway by increasing the ratio of Bax/Bcl-2 and activating cleaved caspase-9, cleaved caspase-3, and cleaved PARP.

Synthesis and activity study of novel N,N-diphenylurea derivatives as IDO1 inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1) has attracted much attention in the field of cancer immunotherapy as an immunomodulatory enzyme. To identify potential IDO1 inhibitors, a novel series of compounds with N,N-diphenylurea and triazole structures were synthesized. The designed compounds underwent organic synthesis, and subsequent enzymatic activity experiments targeting IDO1 confirmed their activity at the molecular level. These experiments provided validation for the efficacy of the designed compounds in inhibiting IDO1, compound 3g exhibited an IC50 value of 1.73 ± 0.97 µM. Further molecular docking study further explained the binding mode and reaction potential of compound 3g with IDO1. Our research has resulted in a series of novel IDO1 inhibitors, which is beneficial to the development of drugs targeting IDO1 in numerous cancer diseases.

Black Truffle Extract Exerts Antidiabetic Effects through Inhibition of Inflammation and Lipid Metabolism Regulation.

Black truffle, a culinary and medical fungus, is highly valued worldwide for its nutritional and therapeutic importance. To enhance the existing knowledge about the beneficial properties, this study investigates the antioxidant, antihyperlipidemic, and anti-inflammatory effects of black truffle extract in in vitro biochemical assays and animal study. Briefly, black truffle extract was administered orally to treat streptozotocin- (STZ-) induced diabetic Wistar rats for 45 days. At the end of the experimental duration, rats were sacrificed to perform biochemical and gene expression analyses related to lipid regulatory and inflammatory pathways. Our results indicated that total cholesterol, triglycerides, free fatty acids, phospholipids, and low-density lipoprotein in different tissues and circulation were significantly increased in diabetic rats. Furthermore, the ß-hydroxy ß-methylglutaryl-CoA enzyme was also significantly increased; lipoprotein lipase and lecithin-cholesterol acyltransferase enzymes were significantly decreased in diabetic rats. However, the above conditions were reversed upon black truffle extract feeding. Furthermore, black truffle extract was also found to downregulate the expression of proinflammatory cytokines (tumor necrosis factor-α and interleukin-6) and lipid regulatory genes (serum regulatory element-binding protein-1 and fatty acid synthase). The truffle extract-treated effects were comparable to glibenclamide and medication commonly used to treat diabetes mellitus. Overall, our results suggested that black truffle possesses strong antihyperlipidemic and anti-inflammatory effects on diabetic rats. These findings will enhance the current knowledge about the therapeutic importance of black truffles. They might be exploited as a possible food supplement or even as a natural source of pharmaceutical agents for diabetes prevention and treatment.

Cu-Mo Bimetal Modulated Multifunctional Carbon Nanofibers Promoting the Polysulfides Conversion for High-Sulfur-Loading Lithium-Sulfur Batteries.

High sulfur loading is essential for achieving high energy density lithium-sulfur (Li-S) batteries. However, serious issues such as low sulfur utilization, poor cycling stability, and sluggish rate performance have been exposed when increasing the sulfur loading for freestanding cathodes. To solve these problems, the adsorption/catalytic ability of high-sulfur-loading cathode toward polysulfides must be improved. Herein, based on excellent properties of cationic MOFs, we proposed that Cu-Mo bimetallic nanoparticles embedded in multifunctional freestanding nitrogen-doped porous carbon nanofibers (Cu-Mo@NPCN) with efficient catalytic sites could be prepared by facile MoO42- anion exchange of cationic MOFs. And, the sulfur embedded in Cu-Mo@NPCN was directly used as self-supporting electrodes, enabling a high areal capacity, good rate performance, and decent cycling stability even under high sulfur loading. The freestanding Cu-Mo@NPCN/10.3S cathode achieves a high volumetric capacity of 1163 mA h cm-3 and a decent areal capacity of 9.3 mA h cm-2 at 0.2 C with a sulfur loading of 10.3 mg cm-2. This work provides an innovative approach for engineering a freestanding sulfur cathode and would forward the development of cationic MOF-derived bimetallic catalysts in various energy storage systems.

Cationic metal-organic framework derived ruthenium-copper nano-alloys in porous carbon to catalytically boost the cycle life of Li-CO2 batteries.

Rechargeable Li-CO2 batteries are an innovative energy storage technology with broad application prospects owing to their superb energy density and ability to capture the greenhouse gas CO2. However, they are still suffering from severe challenges in the formation and decomposition of electrochemically sluggish Li2CO3 discharge products, resulting in poor battery performance. Development of an efficient cathodic electrocatalyst has the potential to address these issues by catalytically boosting the conversion of Li2CO3. Herein, we have designed a Ru-Cu nanoalloy decorated porous carbon (Ru-Cu@NPC) material derived from an anion-exchanged cationic MOF, and it can serve as an efficient cathode electrocatalyst for Li-CO2 batteries. Benefitting from the uniform distribution of ultrafine Ru-Cu nanoalloys with high catalytic performance, Ru-Cu@NPC displays excellent CO2 reduction and evolution activities. Impressively, the Li-CO2 battery with the Ru-Cu@NPC catalyst exhibits a remarkably low potential gap of 0.93 V at 100 mA g-1 and a stable discharge/charge cycling performance of more than 400 cycles at a high current density of 400 mA g-1 within a limiting capacity of 1000 mA h g-1. The study provides an opportunity for the research of cationic MOF derived bimetallic catalysts in the Li-CO2 battery field.

The Effect of Narrative Nursing Intervention on Shame in Elderly Patients with Bladder Cancer after Ileal Bladder Replacement: A Cohort Study.

Background: The standard treatment for bladder cancer (BC) is transurethral resection (TURBt), intravesical chemotherapy, and regular follow-up cystoscopy after surgery. However, some patients experience relapse or progression. Narrative care refers to a nursing model in which nurses put themselves into the patient's position through communication and listening, thereby alleviating the patient's negative emotions. This study analyzed narrative nursing interventions in elderly patients with BC after vesicoileal replacement. Objective: To explore the positive stimulating effect of narrative nursing intervention on the sense of shame in elderly patients with bladder cancer (BC) after ileal bladder replacement. Methods: A total of 60 elderly patients with BC who went through ileal replacement of the bladder from February 2019 to April 2021 in our hospital were enrolled. The patients were divided into the control group and the study group by the arbitrary number table method. The former group received routine care, and the latter group received a narrative nursing intervention model. The nursing satisfaction, stigma score, self-care ability score, SAS score, SDS score, and quality of life score were compared. Results: First, we compared the nursing satisfaction. In the research group, 23 cases were very satisfied, 6 cases were satisfied, and 1 case was normal, and the satisfaction rate was 100.00%. In the control group, 13 cases were very satisfied, 8 cases were satisfied, 4 cases were general, and 5 cases were dissatisfied, with a satisfaction rate of 83.33%. The nursing satisfaction of the research group was significantly higher compared to that of the control group (P < 0.05). Secondly, we compared the stigma scores. The stigma scores of the study group at the time of discharge, 1 month, 3 months, and 6 months after discharge were lower compared to those of the control group (P < 0.05). In terms of the scores of self-care ability, the total scores of self-concept, self-care responsibility, self-care knowledge, self-care skills, and self-care ability of the research group were higher compared to those of the control group (P < 0.05). With regard to SAS scores, before nursing, there was no significant difference exhibited (P > 0.05). After nursing, the patient's SAS score decreased. Compared with the two groups, the SAS scores of the study group at discharge, 1 month, 3 months, and 6 months after discharge were all lower (P < 0.05). In terms of SDS score, there was no significant difference before nursing (P > 0.05). After nursing, the SDS scores of patients decreased. Compared between the two groups, the SDS scores of the study group at the time of discharge, 1 month, 3 months, and 6 months after discharge were lower (P < 0.05). Finally, we compared the life quality scores. Before nursing, there was no significant difference exhibited (P > 0.05). After nursing, the scores of life quality of patients improved. Compared with the two groups, the physical function, psychological function, social function, and healthy self-cognition scores of the research group were all lower compared to those of the control group (P < 0.05). Conclusion: Narrative nursing can reduce anxiety and depression in elderly patients with BC after ileal replacement of the bladder, enhance the quality of life, reduce the patient's stigma, and play a positive motivating role. This nursing model is worthy of promotion in clinic.

Isoquercetin upregulates antioxidant genes, suppresses inflammatory cytokines and regulates AMPK pathway in streptozotocin-induced diabetic rats.

Lifestyle and genetic factors contribute to the initiation of oxidative stress and inflammation in diabetes mellitus (DM). Oxidative stress and lipid peroxidation worked in an orchestrated manner and reported to be strongly associated with the formation of the hyperlipidemic condition in DM patients. Isoquercetin, a bioactive constituent isolated from guava leaves has attracted considerable attention because of its antidiabetic activity. The antidiabetic activity of guava leaves may be due to the presence of isoquercetin at a significant level. However, how isoquercetin regulates different pathways in DM is insufficiently studied. We have selected versatile regulators of oxidative stress and inflammatory pathways to fully analyze if isoquercetin effectively modulated the genes of these pathways. At the end of our experimental duration, rats were dissected and analyzed for the oxidative stress, lipid peroxidation, inflammatory and lipid markers. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is believed to be the key regulator of expression of various antioxidant enzyme genes and it is directly or indirectly related to nuclear factor Kappa- B (NF-kB) and AMP-activated protein kinase (AMPK) pathways. Therefore, we tend to study the effects of STZ on Nrf2, NF-kB and AMPK pathway and how the isoquercetin treatment performs at a molecular level to overcome the burden of DM. The results of our study provided convincing evidence of significant pharmacological properties of isoquercetin in context of its ability to inhibit the oxidative stress elicited by the STZ through generation of the free radicals and regulation of the expression of Nrf2 pathway-associated proteins and genes and it also reduced the burden of hyperlipidemia and inflammation. By taking the above results into consideration isoquercetin can be studied further to elucidate its antidiabetic effects at various levels.

Effects of melatonin implantation on carcass characteristics, meat quality and tissue levels of melatonin and prolactin in Inner Mongolian cashmere goats.

BACKGROUND: Implantation of goats with melatonin can induce cashmere growth and significantly increase cashmere production performance. However, the impact of melatonin implantation on the carcass characteristics, meat quality and related hormone levels in muscle and viscera of cashmere goats has not been studied. This experiment was conducted to determine the effects of melatonin implantation of cashmere goats during the non-growing period on meat quality and related hormone levels in the tissues. It aimed to provide a theoretical basis for the practical application of melatonin in cashmere goat production systems. RESULTS: Melatonin implantation (2 mg/kg live weight) had no influence (P > 0.05) on daily weight gain, carcass weight, dressing percentage, loin muscle area, or the pH, moisture level, crude fat (except for Gluteus muscle) and amino acid content of muscles of cashmere goats. After implantation for 1 month, shear force of Longissimus dorsi and water loss rate of Longissimus dorsi and Biceps femoris of cashmere goats were increased (P < 0.05), whereas the cooking yield of Gluteus muscle was reduced (P < 0.05). The melatonin treatment decreased (P < 0.05) muscle crude protein, Gluteus muscle crude fat and ∑n-3PUFA content and decreased (P < 0.05) ∑n-6PUFA content. However, after 2 months of implantation most of these effects had resolved. Melatonin implantation had no effect (P > 0.05) on the melatonin or prolactin contents of kidney, heart, spleen, liver, Longissimus dorsi, Biceps femoris and Gluteus muscles. Melatonin content of lung tissue was lowered (P < 0.05) and that of prolactin was elevated (P < 0.05) by the melatonin implantation. CONCLUSION: This study has shown little impact of melatonin implantation of cashmere goats on carcass quality. A few meat quality indices i.e., shear force, water loss rate, ∑n-3PUFA, ∑n-6PUFA, and crude protein content of Longissimus dorsi; water loss rate, cooking yield and crude protein content of Biceps femoris; ether extract, crude protein content of Gluteus; were affected briefly (at 1 month of implantation) but these effects were not evident after 2 months of implantation. There was little effect of the melatonin treatments on tissue levels of melatonin or prolactin except in lung.